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Kabil A, Nayyar N, Xu C, Brassard J, Hill LA, Shin SB, Chopra S, Lo B, Li Y, Bal M, Theret M, Rossi FMV, Underhill TM, Hughes MR, McNagny KM. Functional targeting of ILC2s and ILC3s reveals selective roles in intestinal fibrosis and homeostasis. J Exp Med 2025; 222:e20241671. [PMID: 40434419 DOI: 10.1084/jem.20241671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 03/06/2025] [Accepted: 04/28/2025] [Indexed: 05/29/2025] Open
Abstract
Innate lymphoid cells (ILCs) are long-lived, tissue-resident cell analogs to T helper subsets that lack antigen-specific receptors. Understanding the roles of specific ILCs in chronic inflammation and fibrosis has been limited by inadequate tools for selective targeting. Here, we used Il17rb-CreERT2-eGFP and Rorc-Cre strains to selectively delete RORα in ILC2s and ILC3/Th17 cells, respectively. RORα deletion in ILC2s caused significant loss of gastrointestinal ILC2s, increased ILC3 abundance, elevated Th17-type responses, and heightened susceptibility to Crohn's disease-like fibrosis. Conversely, RORα deletion in ILC3/Th17 cells reduced IL-17 production, protecting against fibrosis. Using isolithocholic acid (isoLCA), a microbial secondary bile acid and RORγt inverse agonist, we confirmed the role of ILC3s/Th17 cells in fibrosis. In RORγt reporter and Th17-deficient Rag1-/- mice, isoLCA reduced IL-17 production by ILC3s and attenuated intestinal fibrosis by dampening RORγt-dependent ILC3/Th17 responses. These findings reveal a novel interplay between ILC2s and ILC3s in gut homeostasis and demonstrate the therapeutic potential of targeting RORγt in ILC3s as a strategy for preventing fibrosis.
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MESH Headings
- Animals
- Homeostasis/immunology
- Fibrosis
- Mice
- Immunity, Innate
- Lymphocytes/immunology
- Th17 Cells/immunology
- Th17 Cells/metabolism
- Intestines/pathology
- Intestines/immunology
- Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
- Nuclear Receptor Subfamily 1, Group F, Member 3/genetics
- Nuclear Receptor Subfamily 1, Group F, Member 1/metabolism
- Nuclear Receptor Subfamily 1, Group F, Member 1/genetics
- Mice, Knockout
- Interleukin-17/metabolism
- Mice, Inbred C57BL
- Crohn Disease/immunology
- Crohn Disease/pathology
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Affiliation(s)
- Ahmed Kabil
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Natalia Nayyar
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Chengxi Xu
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Julyanne Brassard
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Lesley A Hill
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada
| | - Samuel B Shin
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Sameeksha Chopra
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Bernard Lo
- Department of Pathology and Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Yicong Li
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Mya Bal
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Marine Theret
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Fabio M V Rossi
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
- The Department of Medical Genetics, University of British Columbia, Vancouver, Canada
| | - T Michael Underhill
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada
| | - Michael R Hughes
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Kelly M McNagny
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
- The Department of Medical Genetics, University of British Columbia, Vancouver, Canada
- The Center for Heart Lung Innovation, St Paul's Hospital , Vancouver, Canada
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2
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Pastras P, Aggeletopoulou I, Papantoniou K, Triantos C. Targeting the IL-23 Receptor Gene: A Promising Approach in Inflammatory Bowel Disease Treatment. Int J Mol Sci 2025; 26:4775. [PMID: 40429917 DOI: 10.3390/ijms26104775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2025] [Revised: 05/09/2025] [Accepted: 05/14/2025] [Indexed: 05/29/2025] Open
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's Disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation of the gastrointestinal tract. A key component of the inflammatory pathway in IBD is interleukin 23 (IL-23), which promotes the differentiation and maintenance of Th17 cells. These cells are major contributors to intestinal inflammation and the release of pro-inflammatory cytokines. A dysregulated IL-23/Th17 axis can lead to excessive gut inflammation. Notably, IL-23 affects Th17 cell responses differently in UC and CD, fostering IL-17 production in UC and interferon-gamma (IFN-γ) production in CD. Genetic studies have pinpointed specific variants of the IL-23 receptor (IL23R) gene that confer protection against IBD. The R381Q (rs11209026) variant has been linked to a reduced risk of developing both CD and UC. Additionally, other variants, such as G149R (rs76418789) and V362I (rs41313262), inhibit IL23R function by disrupting intracellular trafficking and protein stability. This disruption results in decreased phosphorylation of downstream signal transducers, such as STAT3 and STAT4, and reduced IL23R expression on the cell surface, ultimately dampening the activation of pro-inflammatory pathways. The protective effects of these genetic variants underscore the IL-23/IL23R pathway as a significant therapeutic target in IBD management. Therapies designed to modulate this pathway have the potential to reduce pro-inflammatory cytokine production and enhance anti-inflammatory mechanisms. Ongoing research into the IL23R gene and its variants continues to provide valuable insights, paving the way for more targeted and effective treatments for IBD patients.
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Affiliation(s)
- Ploutarchos Pastras
- Division of Gastroenterology, Department of Internal Medicine, University of Patras, 26504 Patras, Greece
| | - Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University of Patras, 26504 Patras, Greece
| | - Konstantinos Papantoniou
- Division of Gastroenterology, Department of Internal Medicine, University of Patras, 26504 Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University of Patras, 26504 Patras, Greece
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3
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LEE WK, WAN HT, CHENG Z, CHAN WY, LAM TKY, LAI KP, WANG J, CAI Z, WONG CKC. Impact of PFOS Exposure on Murine Fetal Hematopoietic Stem Cells, Associated with Intrauterine Metabolic Perturbation. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2025; 59:5496-5509. [PMID: 40082253 PMCID: PMC11948485 DOI: 10.1021/acs.est.5c02623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 03/06/2025] [Accepted: 03/07/2025] [Indexed: 03/16/2025]
Abstract
This study hypothesized that perfluorooctanesulfonate (PFOS) exposure disrupts maternal-fetal metabolism, affecting fetal liver hematopoietic stem cell (FL-HSC) development. Pregnant mice received PFOS (0.3 and 3 μg/g bw) and were sacrificed on gestation day 14.5. Metabolomic analysis of maternal plasma revealed disruptions in steroid hormone, purine, carbohydrate, and amino acid metabolism, which aligned with the enriched pathways in amniotic fluid (AF). FL analysis indicated increased purine metabolism and disrupted glucose and amino acid metabolism. FL exhibited higher levels of polyunsaturated fatty acids, glycolytic and TCA metabolites, and pro-inflammatory cytokine IL-23, crucial for hematopoiesis regulation. Transcriptomic analysis of FL-HSCs revealed disturbances in the PPAR signaling pathway, pyruvate metabolism, oxidative phosphorylation, and amino acid metabolism, correlating with FL metabolic changes. Metabolomic analysis indicated significant rises in glycerophospholipid and vitamin B6 metabolism related to HSC expansion and differentiation. Flow cytometric analysis confirmed increased HSC populations and progenitor activation for megakaryocyte, erythrocyte, and lymphocyte lineages. The CFU assay showed a significant increase in BFU-E and CFU-G, but a decrease in CFU-GM in FL-HSCs from the H-PFOS group, indicating altered differentiation potential. These findings provide for the first time insights into the effects of PFOS on maternal-fetal metabolism and fetal hematopoiesis, highlighting implications for pollution-affected immune functions.
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Affiliation(s)
- Wang Ka LEE
- Croucher
Institute for Environmental Sciences, Department of Biology, Hong Kong Baptist University, Hong Kong SAR
| | - Hin Ting WAN
- Croucher
Institute for Environmental Sciences, Department of Biology, Hong Kong Baptist University, Hong Kong SAR
| | - Zheyu CHENG
- Croucher
Institute for Environmental Sciences, Department of Biology, Hong Kong Baptist University, Hong Kong SAR
| | - Wing Yee CHAN
- Croucher
Institute for Environmental Sciences, Department of Biology, Hong Kong Baptist University, Hong Kong SAR
| | - Thomas Ka Yam LAM
- State
Key Laboratory in Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong SAR
| | - Keng Po LAI
- Department
of Applied Science, Hong Kong Metropolitan
University, Hong Kong SAR
| | - Jianing WANG
- State
Key Laboratory in Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong SAR
| | - Zongwei CAI
- State
Key Laboratory in Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong SAR
| | - Chris Kong Chu WONG
- Croucher
Institute for Environmental Sciences, Department of Biology, Hong Kong Baptist University, Hong Kong SAR
- State
Key Laboratory in Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong SAR
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Singh A, Chia JJ, Rao DS, Hoffmann A. Population dynamics modeling reveals that myeloid bias involves both HSC differentiation and progenitor proliferation biases. Blood 2025; 145:1293-1308. [PMID: 39791596 PMCID: PMC11952015 DOI: 10.1182/blood.2024025598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 11/01/2024] [Accepted: 11/20/2024] [Indexed: 01/12/2025] Open
Abstract
ABSTRACT Aging and chronic inflammation are associated with overabundant myeloid-primed multipotent progenitors (MPPs) among hematopoietic stem and progenitor cells (HSPCs). Although hematopoietic stem cell (HSC) differentiation bias has been considered a primary cause of myeloid bias, whether it is sufficient has not been quantitatively evaluated. Here, we analyzed bone marrow data from the IκB- (Nfkbia+/-Nfkbib-/-Nfkbie-/-) mouse model of inflammation with elevated NFκB activity, which reveals increased myeloid-biased MPPs. We interpreted these data with differential equation models of population dynamics to identify alterations of HSPC proliferation and differentiation rates. This analysis revealed that short-term HSC differentiation bias alone is likely insufficient to account for the increase in myeloid-biased MPPs. To explore additional mechanisms, we used single-cell RNA sequencing (scRNA-seq) measurements of IκB- and wild-type HSPCs to track the continuous differentiation trajectories from HSCs to erythrocyte/megakaryocyte, myeloid, and lymphoid primed progenitors. Fitting a partial differential equations model of population dynamics to these data revealed not only less lymphoid-fate specification among HSCs but also increased expansion of early myeloid-primed progenitors. Differentially expressed genes along the differentiation trajectories supported increased proliferation among these progenitors. These findings were conserved when wild-type HSPCs were transplanted into IκB- recipients, indicating that an inflamed bone marrow microenvironment is a sufficient driver. We then applied our analysis pipeline to scRNA-seq measurements of HSPCs isolated from aged mice and human patients with myeloid neoplasms. These analyses identified the same myeloid-primed progenitor expansion as in the IκB- models, suggesting that it is a common feature across different settings of myeloid bias.
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Affiliation(s)
- Apeksha Singh
- Signaling Systems Laboratory, Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA
- Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA
| | - Jennifer J. Chia
- Signaling Systems Laboratory, Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA
- Broad Stem Cell Research Center, University of California, Los Angeles, CA
| | - Dinesh S. Rao
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA
- Broad Stem Cell Research Center, University of California, Los Angeles, CA
| | - Alexander Hoffmann
- Signaling Systems Laboratory, Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA
- Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA
- Broad Stem Cell Research Center, University of California, Los Angeles, CA
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5
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Guo R, Xie X, Ren Q, Liew PX. New insights on extramedullary granulopoiesis and neutrophil heterogeneity in the spleen and its importance in disease. J Leukoc Biol 2025; 117:qiae220. [PMID: 39514106 DOI: 10.1093/jleuko/qiae220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Indexed: 11/16/2024] Open
Abstract
Neutrophils are traditionally viewed as uncomplicated exterminators that arrive quickly at sites of infection, kill pathogens, and then expire. However, recent studies employing modern transcriptomics coupled with novel imaging modalities have discovered that neutrophils exhibit significant heterogeneity within organs and have complex functional roles ranging from tissue homeostasis to cancer and chronic pathologies. This has revised the view that neutrophils are simplistic butchers, and there has been a resurgent interest in neutrophils. The spleen was described as a granulopoietic organ more than 4 decades ago, and studies indicate that neutrophils are briefly retained in the spleen before returning to circulation after proliferation. Transcriptomic studies have discovered that splenic neutrophils are heterogeneous and distinct compared with those in blood. This suggests that a unique hematopoietic niche exists in the splenic microenvironment, i.e., capable of programming neutrophils in the spleen. During severe systemic inflammation with an increased need of neutrophils, the spleen can adapt by producing neutrophils through emergency granulopoiesis. In this review, we describe the structure and microanatomy of the spleen and examine how cells within the splenic microenvironment help to regulate splenic granulopoiesis. A focus is placed on exploring the increase in splenic granulopoiesis to meet host needs during infection and inflammation. Emerging technologies such as single-cell RNA sequencing, which provide valuable insight into splenic neutrophil development and heterogeneity, are also discussed. Finally, we examine how tumors subvert this natural pathway in the spleen to generate granulocytic suppressor cells to promote tumor growth.
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Affiliation(s)
- Rongxia Guo
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuchang District, Wuhan, Hubei 430071, China
| | - Xuemei Xie
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 77 Ave Louis Pasteur, Boston, MA 02115, United States
| | - Qian Ren
- State Key Laboratory of Experimental Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Heping District, Tianjin 300020, China
- Tianjin Institutes of Health Science, Chinese Academy of Medical Sciences, 288 Nanjing Road, Heping District, Tianjin 300020, China
| | - Pei Xiong Liew
- Immunology Center of Georgia, Augusta University, 1410 Laney Walker Blvd, Augusta, GA 30912, United States
- Department of Cellular Biology and Anatomy, Augusta University, 1434 Laney Walker Blvd, Augusta, GA 30912, United States
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6
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Viola MF, Mass E. Bacterial translocation promotes trained immunity. Immunity 2025; 58:268-270. [PMID: 39938478 DOI: 10.1016/j.immuni.2025.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 01/10/2025] [Indexed: 02/14/2025]
Abstract
Can bacteria that breach mucosal barriers drive long-lasting changes in immunity? In this issue of Immunity, Robles-Vera et al. describe how, in the context of colitis, bacteria breaching the intestinal barrier reprogram precursors in the bone marrow via Mincle-dependent signaling.
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Affiliation(s)
- Maria Francesca Viola
- Developmental Biology of the Immune System, Life & Medical Sciences (LIMES) Institute, University of Bonn, 53115 Bonn, Germany
| | - Elvira Mass
- Developmental Biology of the Immune System, Life & Medical Sciences (LIMES) Institute, University of Bonn, 53115 Bonn, Germany.
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7
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Madel MB, Ibáñez L, Ciucci T, Halper J, Boutin A, Beldi G, Lavanant AC, Garchon HJ, Rouleau M, Mueller CG, Peyrin-Biroulet L, Moulin D, Blin-Wakkach C, Wakkach A. Dysregulated myeloid differentiation in colitis is induced by inflammatory osteoclasts in a TNFα-dependent manner. Mucosal Immunol 2025; 18:90-104. [PMID: 39332768 DOI: 10.1016/j.mucimm.2024.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 09/14/2024] [Accepted: 09/24/2024] [Indexed: 09/29/2024]
Abstract
Inflammatory bowel disease (IBD) is characterized by very severe intestinal inflammation associated with extra-intestinal manifestations. One of the most critical ones is bone destruction, which remains a major cause of morbidity and a risk factor for osteopenia and osteoporosis in IBD patients. In various mouse models of IBD, we and other have demonstrated concomitant bone loss due to a significant increase in osteoclast activity. Besides bone resorption, osteoclasts are known to control hematopoietic niches in vivo and modulate inflammatory responses in vitro, suggesting they may participate in chronic inflammation in vivo. Here, using different models of colitis, we showed that osteoclast inhibition significantly reduced disease severity and that induction of osteoclast differentiation by RANKL contributed to disease worsening. Our results demonstrate a direct link between osteoclast activity and myeloid cell accumulation in the intestine during colitis. RNAseq analysis of osteoclasts from colitic mice revealed overexpression of genes involved in the remodeling of hematopoietic stem cell niches. We also demonstrated that osteoclasts induced hematopoietic progenitor proliferation accompanied by a myeloid skewing in the early phases of colitis, which was confirmed in a model of RANKL-induced osteoclastogenesis. Mechanistically, inhibition of TNF-α reduced the induction of myeloid skewing by OCL both in vitro and in vivo. Lastly, we observed that osteoclastic activity and the proportion of myeloid cells in the blood are positively correlated in patients with Crohn's disease. Collectively, our results shed light on a new role of osteoclasts in colitis in vivo, demonstrating they exert their colitogenic activity through an early action on hematopoiesis, leading to an increase in myelopoiesis sustaining gut inflammation.
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Affiliation(s)
| | - Lidia Ibáñez
- Université Côte d'Azur, CNRS, LP2M, Nice, France
| | - Thomas Ciucci
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Julia Halper
- Université Côte d'Azur, CNRS, LP2M, Nice, France
| | | | - Ghada Beldi
- Université Côte d'Azur, CNRS, LP2M, Nice, France
| | - Alice C Lavanant
- CNRS UPR 3572, IBMC, University of Strasbourg, 67000 Strasbourg, France
| | - Henri-Jean Garchon
- Université Paris-Saclay, UVSQ, INSERM, Infection et inflammation, 78180 Montigny-Le-Bretonneux, France
| | | | | | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, IHU INFINY, CHRU Nancy, F-54500 Vandœuvre-lès-Nancy, France; Université de Lorraine, INSERM, NGERE, F-54500 Vandoeuvre les Nancy, France
| | - David Moulin
- Université de Lorraine, CNRS, IMoPA, F-54500 Vandœuvre Les Nancy, France; IHU INFINY, Contrat d'interface, CHRU Nancy, France
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8
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Horn V, Cancino CA, Steinheuer LM, Obermayer B, Fritz K, Nguyen AL, Juhran KS, Plattner C, Bösel D, Oldenburg L, Burns M, Schulz AR, Saliutina M, Mantzivi E, Lissner D, Conrad T, Mashreghi MF, Zundler S, Sonnenberg E, Schumann M, Haag LM, Beule D, Flatz L, Trajanoski Z, D'Haens G, Weidinger C, Mei HE, Siegmund B, Thurley K, Hegazy AN. Multimodal Profiling of Peripheral Blood Identifies Proliferating Circulating Effector CD4 + T Cells as Predictors for Response to Integrin α4β7-Blocking Therapy in Inflammatory Bowel Disease. Gastroenterology 2025; 168:327-343. [PMID: 39343250 DOI: 10.1053/j.gastro.2024.09.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 09/06/2024] [Accepted: 09/18/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND & AIMS Despite the success of biological therapies in treating inflammatory bowel disease, managing patients remains challenging due to the absence of reliable predictors of therapy response. METHODS In this study, we prospectively sampled 2 cohorts of patients with inflammatory bowel disease receiving the anti-integrin α4β7 antibody vedolizumab. Samples were subjected to mass cytometry; single-cell RNA sequencing; single-cell B and T cell receptor sequencing (BCR/TCR-seq); serum proteomics; and multiparametric flow cytometry to comprehensively assess vedolizumab-induced immunologic changes in the peripheral blood and their potential associations with treatment response. RESULTS Vedolizumab treatment led to substantial alterations in the abundance of circulating immune cell lineages and modified the T-cell receptor diversity of gut-homing CD4+ memory T cells. Through integration of multimodal parameters and machine learning, we identified a significant increase in proliferating CD4+ memory T cells among nonresponders before treatment compared with responders. This predictive T-cell signature demonstrated an activated T-helper 1/T-helper 17 cell phenotype and exhibited elevated levels of integrin α4β1, potentially making these cells less susceptible to direct targeting by vedolizumab. CONCLUSIONS These findings provide a reliable predictive classifier with significant implications for personalized inflammatory bowel disease management.
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Affiliation(s)
- Veronika Horn
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Camila A Cancino
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Lisa M Steinheuer
- Institute of Experimental Oncology, Biomathematics Division, University Hospital Bonn, Bonn, Germany
| | - Benedikt Obermayer
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Core Unit Bioinformatics, Berlin, Germany
| | - Konstantin Fritz
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Anke L Nguyen
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Department of Gastroenterology, Central Clinical School, Monash University and Alfred Health, Melbourne, Victoria, Australia
| | - Kim Susan Juhran
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Christina Plattner
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Diana Bösel
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Lotte Oldenburg
- Department of Gastroenterology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Marie Burns
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Axel Ronald Schulz
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Mariia Saliutina
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Eleni Mantzivi
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Donata Lissner
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Thomas Conrad
- Genomics Technology Platform, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Core Unit Genomics, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Mir-Farzin Mashreghi
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany; German Center for Child and Adolescent Health (DZKJ), Partner Site Berlin, Berlin, Germany
| | - Sebastian Zundler
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Elena Sonnenberg
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Michael Schumann
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Lea-Maxie Haag
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Dieter Beule
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Core Unit Bioinformatics, Berlin, Germany
| | - Lukas Flatz
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland; Department of Dermatology, University Hospital Tübingen, University of Tübingen, Tübingen, Germany
| | - Zlatko Trajanoski
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Geert D'Haens
- Department of Gastroenterology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Carl Weidinger
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Henrik E Mei
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Britta Siegmund
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Kevin Thurley
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany; Institute of Experimental Oncology, Biomathematics Division, University Hospital Bonn, Bonn, Germany.
| | - Ahmed N Hegazy
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin Institute of Health Academy, Clinician Scientist Program, Berlin, Germany.
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9
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Fachi JL, de Oliveira S, Gilfillan S, Antonova AU, Hou J, Vinolo MAR, Colonna M. NKp46 + ILC3s promote early neutrophil defense against Clostridioides difficile infection through GM-CSF secretion. Proc Natl Acad Sci U S A 2024; 121:e2416182121. [PMID: 39475653 PMCID: PMC11551360 DOI: 10.1073/pnas.2416182121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 10/02/2024] [Indexed: 11/07/2024] Open
Abstract
Clostridioides difficile infection (CDI) is a common cause of antibiotic-associated colitis. C. difficile proliferates and produces toxins that damage the colonic epithelium, leading to symptoms ranging from mild diarrhea to severe pseudomembranous colitis. The host's innate response to CDI occurs in two phases: an early phase in which neutrophils reduce the bacterial load and a late phase involving repair mechanisms to restore epithelial integrity. Group 3 innate lymphoid cells (ILC3s) are crucial in protecting the gut from CDI. Previous studies have shown that ILC3-derived IL-22 is essential in the late phase of CDI for epithelial repair and maintaining an intestinal microbiota that competes with C. difficile, preventing its expansion. Our study finds that ILC3s also protect during the early stages of CDI by sustaining neutrophils through GM-CSF. Less neutrophil production, accumulation, and activation was evident in ILC3-deficient mice than in wild-type (WT) mice, which led to exacerbated symptoms, impaired pathogen clearance, a compromised epithelial barrier, and increased mortality. The adoptive transfer of ILC3s into ILC3-deficient mice restored neutrophil responses and improved disease outcomes. Both in vitro and in vivo experiments revealed that GM-CSF production by ILC3s is crucial for neutrophil production and effective resistance during CDI. Using mice lacking NKp46+ ILC3s, we found that this subset significantly contributes to GM-CSF production in CDI. These findings highlight the critical role of the ILC3-neutrophil connection in early innate responses to CDI. Enhancing ILC3 production of GM-CSF could be a promising strategy for improving host defense against CDI and other enteric infections.
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Affiliation(s)
- José L. Fachi
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO63110
| | - Sarah de Oliveira
- Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, University of Campinas, Campinas, SP13083-862, Brazil
| | - Susan Gilfillan
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO63110
| | - Alina Ulezko Antonova
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO63110
| | - JinChao Hou
- Department of Anesthesiology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou310052, China
| | - Marco A. R. Vinolo
- Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, University of Campinas, Campinas, SP13083-862, Brazil
| | - Marco Colonna
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO63110
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10
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Ohara D, Takeuchi Y, Hirota K. Type 17 immunity: novel insights into intestinal homeostasis and autoimmune pathogenesis driven by gut-primed T cells. Cell Mol Immunol 2024; 21:1183-1200. [PMID: 39379604 PMCID: PMC11528014 DOI: 10.1038/s41423-024-01218-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 09/11/2024] [Indexed: 10/10/2024] Open
Abstract
The IL-23 signaling pathway in both innate and adaptive immune cells is vital for orchestrating type 17 immunity, which is marked by the secretion of signature cytokines such as IL-17, IL-22, and GM-CSF. These proinflammatory mediators play indispensable roles in maintaining intestinal immune equilibrium and mucosal host defense; however, their involvement has also been implicated in the pathogenesis of chronic inflammatory disorders, such as inflammatory bowel diseases and autoimmunity. However, the implications of type 17 immunity across diverse inflammation models are complex. This review provides a comprehensive overview of the multifaceted roles of these cytokines in maintaining gut homeostasis and in perturbing gut barrier integrity, leading to acute and chronic inflammation in various models of gut infection and colitis. Additionally, this review focuses on type 17 immunity interconnecting multiple organs in autoimmune conditions, with a particular emphasis on the pathogenesis of autoimmune arthritis and neuroinflammation driven by T cells primed within the gut microenvironment.
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Affiliation(s)
- Daiya Ohara
- Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Yusuke Takeuchi
- Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Keiji Hirota
- Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
- ImmunoSensation Cluster of Excellence, University of Bonn, Bonn, Germany.
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11
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Pearson CF, Maloy KJ. Update: Induction of Inflammatory Bowel Disease in Immunodeficient Mice by Injection of Naïve CD4 + T cells (T Cell Transfer Model of Colitis). Curr Protoc 2024; 4:e1092. [PMID: 39007482 DOI: 10.1002/cpz1.1092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
The intestinal inflammation induced by injection of naïve CD4+ T cells into lymphocyte-deficient hosts (more commonly known as the T cell transfer model of colitis) shares many features of idiopathic inflammatory bowel disease (IBD) in humans, such as epithelial cell hyperplasia, crypt abscess formation, and dense lamina propria lymphocyte infiltration. As such, it provides a useful tool for studying mucosal immune regulation as it relates to the pathogenesis and treatment of IBD in humans. In the IBD model described here, colitis is induced in Rag (recombination-activating gene)-deficient mice by reconstitution of these mice with naïve CD4+CD45RBhi T cells through adoptive T cell transfer. Although different recipient hosts of cell transfer can be used, Rag-deficient mice are the best characterized and support studies that are both flexible and reproduceable. As described in the Basic Protocol, in most studies the transferred cells consist of naïve CD4+ T cells (CD45RBhi T cells) derived by fluorescence-activated cell sorting from total CD4+ T cells previously purified using immunomagnetic negative selection beads. In a Support Protocol, methods to characterize colonic disease progression are described, including the monitoring of weight loss and diarrhea and the histological assessment of colon pathology. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Induction of IBD in Rag-deficient mice by the transfer of naïve CD4+CD45RBhi T cells Support Protocol: Monitoring development of colitis.
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Affiliation(s)
- Claire F Pearson
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Kevin J Maloy
- School of Infection and Immunity, University of Glasgow, Glasgow, UK
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12
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Rivera-Torruco G, Muench MO, Valle-Rios R. Exploring extramedullary hematopoiesis: unraveling the hematopoietic microenvironments. FRONTIERS IN HEMATOLOGY 2024; 3:1371823. [PMID: 39668982 PMCID: PMC11636351 DOI: 10.3389/frhem.2024.1371823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2024]
Abstract
Hematopoiesis is a process by which all blood cells are formed. The mechanisms controlling it have been studied for decades. Surprisingly, while hematopoietic stem cells are among the most extensively studied stem cell types, the complete understanding of how they are regulated during development, adulthood, or in non-homeostatic conditions remains elusive. In this review, our primary focus is on research findings that explore where hematopoietic precursors are found in adults outside their primary niches in the bone marrow. This phenomenon is termed extramedullary hematopoiesis (EMH). Early in development hematopoietic stem cells migrate through different regions within and outside the embryo and later the fetus. Although, the primary home for hematopoietic progenitors is the adult bone marrow, it is now recognized that other adult organs may act as hematopoietic progenitor reservoirs both in mice and humans. The first reports about this topic were principally originated from clinical observations, in cases where the bone marrow was malfunctioning, leading to an aberrant hematopoiesis outside the bone marrow. It is worth highlighting that those extramedullary organs, like the small intestine or fat tissue, contain subsets of fully functioning hematopoietic progenitors demonstrated by both in vitro and in vivo studies. Nonetheless, there are still some unanswered questions regarding the source of these cells, how they differ in function compared to their counterparts in the bone marrow, and the specific roles they play within the tissues where they are located.
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Affiliation(s)
- Guadalupe Rivera-Torruco
- Cell Therapy Core, Vitalant Research Institute, San Francisco, CA, United States
- Department of Laboratory Medicine, Medical Center, University of California, San Francisco, San Francisco, CA, United States
| | - Marcus O. Muench
- Cell Therapy Core, Vitalant Research Institute, San Francisco, CA, United States
- Department of Laboratory Medicine, Medical Center, University of California, San Francisco, San Francisco, CA, United States
| | - Ricardo Valle-Rios
- Research Division, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
- Laboratorio de Investigación en Inmunología y Proteómica, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
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13
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Goswami M, Bose PD. Gut microbial dysbiosis in the pathogenesis of leukemia: an immune-based perspective. Exp Hematol 2024; 133:104211. [PMID: 38527589 DOI: 10.1016/j.exphem.2024.104211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 03/04/2024] [Accepted: 03/16/2024] [Indexed: 03/27/2024]
Abstract
Leukemias are a set of clonal hematopoietic malignant diseases that develop in the bone marrow. Several factors influence leukemia development and progression. Among these, the gut microbiota is a major factor influencing a wide array of its processes. The gut microbial composition is linked to the risk of tumor development and the host's ability to respond to treatment, mostly due to the immune-modulatory effects of their metabolites. Despite such strong evidence, its role in the development of hematologic malignancies still requires attention of investigators worldwide. In this review, we make an effort to discuss the role of host gut microbiota-immune crosstalk in leukemia development and progression. Additionally, we highlight certain recently developed strategies to modify the gut microbial composition that may help to overcome dysbiosis in leukemia patients in the near future.
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Affiliation(s)
- Mayuri Goswami
- Department of Molecular Biology and Biotechnology, Cotton University, Panbazar, Guwahati, Assam, India
| | - Purabi Deka Bose
- Department of Molecular Biology and Biotechnology, Cotton University, Panbazar, Guwahati, Assam, India.
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14
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Zervopoulou E, Grigoriou M, Doumas SA, Yiannakou D, Pavlidis P, Gasparoni G, Walter J, Filia A, Gakiopoulou H, Banos A, Mitroulis I, Boumpas DT. Enhanced medullary and extramedullary granulopoiesis sustain the inflammatory response in lupus nephritis. Lupus Sci Med 2024; 11:e001110. [PMID: 38471723 DOI: 10.1136/lupus-2023-001110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 02/20/2024] [Indexed: 03/14/2024]
Abstract
OBJECTIVES In SLE, deregulation of haematopoiesis is characterised by inflammatory priming and myeloid skewing of haematopoietic stem and progenitor cells (HSPCs). We sought to investigate the role of extramedullary haematopoiesis (EMH) as a key player for tissue injury in systemic autoimmune disorders. METHODS Transcriptomic analysis of bone marrow (BM)-derived HSPCs from patients with SLE and NZBW/F1 lupus-prone mice was performed in combination with DNA methylation profile. Trained immunity (TI) was induced through β-glucan administration to the NZBW/F1 lupus-prone model. Disease activity was assessed through lupus nephritis (LN) histological grading. Colony-forming unit assay and adoptive cell transfer were used to assess HSPCs functionalities. RESULTS Transcriptomic analysis shows that splenic HSPCs carry a higher inflammatory potential compared with their BM counterparts. Further induction of TI, through β-glucan administration, exacerbates splenic EMH, accentuates myeloid skewing and worsens LN. Methylomic analysis of BM-derived HSPCs demonstrates myeloid skewing which is in part driven by epigenetic tinkering. Importantly, transcriptomic analysis of human SLE BM-derived HSPCs demonstrates similar findings to those observed in diseased mice. CONCLUSIONS These data support a key role of granulocytes derived from primed HSPCs both at medullary and extramedullary sites in the pathogenesis of LN. EMH and TI contribute to SLE by sustaining the systemic inflammatory response and increasing the risk for flare.
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Affiliation(s)
- Eleni Zervopoulou
- Autoimmunity and Inflammation Laboratory, Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
- 4th Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Grigoriou
- Autoimmunity and Inflammation Laboratory, Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
- 1st Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace School of Health Sciences, Alexandroupoli, Greece
| | - Stavros A Doumas
- Autoimmunity and Inflammation Laboratory, Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
- 4th Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Danae Yiannakou
- Institute of Computer Science, Foundation of Research and Technology Hellas, Heraklion, Greece
| | - Pavlos Pavlidis
- Institute of Computer Science, Foundation of Research and Technology Hellas, Heraklion, Greece
| | - Gilles Gasparoni
- Department of Genetics-Epigenetics, Saarland University, Saarbrucken, Germany
| | - Jörn Walter
- Department of Genetics-Epigenetics, Saarland University, Saarbrucken, Germany
| | - Anastasia Filia
- Autoimmunity and Inflammation Laboratory, Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
- 1st Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace School of Health Sciences, Alexandroupoli, Greece
| | - Harikleia Gakiopoulou
- 1st Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Aggelos Banos
- Autoimmunity and Inflammation Laboratory, Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
| | - Ioannis Mitroulis
- 1st Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace School of Health Sciences, Alexandroupoli, Greece
| | - Dimitrios T Boumpas
- Autoimmunity and Inflammation Laboratory, Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
- 4th Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
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15
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Wang Y, Morishima T, Sezaki M, Sato R, Nakato G, Fukuda S, Kobiyama K, Ishii KJ, Li Y, Takizawa H. Akkermansia muciniphila induces slow extramedullary hematopoiesis via cooperative IL-1R/TLR signals. EMBO Rep 2023; 24:e57485. [PMID: 37870318 PMCID: PMC10702838 DOI: 10.15252/embr.202357485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 10/03/2023] [Accepted: 10/06/2023] [Indexed: 10/24/2023] Open
Abstract
Bacterial infections can activate and mobilize hematopoietic stem and progenitor cells (HSPCs) from the bone marrow (BM) to the spleen, a process termed extramedullary hematopoiesis (EMH). Recent studies suggest that commensal bacteria regulate not only the host immune system but also hematopoietic homeostasis. However, the impact of gut microbes on hematopoietic pathology remains unclear. Here, we find that systemic single injections of Akkermansia muciniphila (A. m.), a mucin-degrading bacterium, rapidly activate BM myelopoiesis and slow but long-lasting hepato-splenomegaly, characterized by the expansion and differentiation of functional HSPCs, which we term delayed EMH. Mechanistically, delayed EMH triggered by A. m. is mediated entirely by the MYD88/TRIF innate immune signaling pathway, which persistently stimulates splenic myeloid cells to secrete interleukin (IL)-1α, and in turn, activates IL-1 receptor (IL-1R)-expressing splenic HSPCs. Genetic deletion of Toll-like receptor-2 and -4 (TLR2/4) or IL-1α partially diminishes A. m.-induced delayed EMH, while inhibition of both pathways alleviates splenomegaly and EMH. Our results demonstrate that cooperative IL-1R- and TLR-mediated signals regulate commensal bacteria-driven EMH, which might be relevant for certain autoimmune disorders.
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Affiliation(s)
- Yuxin Wang
- Department of Hematology, Zhujiang HospitalSouthern Medical UniversityGuangzhouChina
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
| | - Tatsuya Morishima
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
- Laboratory of Hematopoietic Stem Cell Engineering, IRCMSKumamoto UniversityKumamotoJapan
| | - Maiko Sezaki
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
- Laboratory of Hematopoietic Stem Cell Engineering, IRCMSKumamoto UniversityKumamotoJapan
| | - Ryo Sato
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
| | - Gaku Nakato
- Gut Environmental Design GroupKanagawa Institute of Industrial Science and TechnologyAtsugiJapan
| | - Shinji Fukuda
- Gut Environmental Design GroupKanagawa Institute of Industrial Science and TechnologyAtsugiJapan
- Institute for Advanced Biosciences (IAB)Keio UniversityTokyoJapan
- Transborder Medical Research CenterUniversity of TsukubaTsukubaJapan
| | - Kouji Kobiyama
- Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical ScienceThe University of TokyoTokyoJapan
- International Vaccine Design Center, The Institute of Medical ScienceThe University of TokyoTokyoJapan
| | - Ken J Ishii
- Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical ScienceThe University of TokyoTokyoJapan
- International Vaccine Design Center, The Institute of Medical ScienceThe University of TokyoTokyoJapan
| | - Yuhua Li
- Department of Hematology, Zhujiang HospitalSouthern Medical UniversityGuangzhouChina
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)GuangzhouChina
| | - Hitoshi Takizawa
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
- Center for Metabolic Regulation of Healthy Aging (CMHA)Kumamoto UniversityKumamotoJapan
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16
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Li X, Li Z, Cai D, Li Y, Zhu Y, Jiao R, Lai C, Sun J, Bai W. Vitisin A, as a Type of Pyranoanthocyanin, Suppresses Inflammation by Restricting Hematopoietic Stem Cell Differentiation toward Monocytes in Bone Marrow. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:15048-15063. [PMID: 37811833 DOI: 10.1021/acs.jafc.3c03119] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Hematopoietic stem and progenitor cells (HSPCs) could be differentiated into mature myeloid and lymphoid cells, maintaining the requirements of immune cells. Atherosclerosis and ulcerative colitis (UC) drive HSPC homeostasis destruction, which triggers expansive HSPC proliferation and Ly6Chi monocyte production, contributing to aggravated inflammation. Vitisin A belongs to the anthocyanin derivatives with excellent stability and bioactivity in vitro. However, there is no report about the anti-inflammation of Vitisin A via reprogramming HSPC differentiation toward monocytes. In this study, we found that Vitisin A presents anti-inflammatory ability during the development of atherosclerosis and UC by depressing Ly6Chi monocyte production from bone marrow. This performance depended on restricted HSPC differentiation, which suggested that Vitisin A participated in monocyte generation and carried out the immunomodulation. Together, Vitisin A ameliorates inflammation during atherosclerosis and UC via the suppressed differentiation of HSPCs toward monocytes, which could be considered an ideal functional component with immunomodulatory effects.
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Affiliation(s)
- Xusheng Li
- The Sixth Affiliated Hospital, Jinan University, Dongguan 523576, P. R. China
- Department of Food Science and Engineering, Institute of Food Safety and Nutrition, Jinan University, Guangzhou 510632, P. R. China
| | - Zhenhua Li
- Department of Systems Biomedical Sciences, School of Medicine, Jinan University, Guangzhou 510632, P. R. China
| | - Dongbao Cai
- Department of Food Science and Engineering, Institute of Food Safety and Nutrition, Jinan University, Guangzhou 510632, P. R. China
| | - Yawen Li
- Department of Food Science and Engineering, Institute of Food Safety and Nutrition, Jinan University, Guangzhou 510632, P. R. China
| | - Yuanqin Zhu
- Department of Food Science and Engineering, Institute of Food Safety and Nutrition, Jinan University, Guangzhou 510632, P. R. China
| | - Rui Jiao
- Department of Food Science and Engineering, Institute of Food Safety and Nutrition, Jinan University, Guangzhou 510632, P. R. China
| | - Caiyong Lai
- The Sixth Affiliated Hospital, Jinan University, Dongguan 523576, P. R. China
- Department of Urology, Institute of Kidney Surgery, The First Affiliated Hospital, Jinan University, Guangzhou 510632, P. R. China
| | - Jianxia Sun
- School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, P. R. China
| | - Weibin Bai
- Department of Food Science and Engineering, Institute of Food Safety and Nutrition, Jinan University, Guangzhou 510632, P. R. China
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17
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Thompson B, Lu S, Revilla J, Uddin MJ, Oakland DN, Brovero S, Keles S, Bresnick EH, Petri WA, Burgess SL. Secondary bile acids function through the vitamin D receptor in myeloid progenitors to promote myelopoiesis. Blood Adv 2023; 7:4970-4982. [PMID: 37276450 PMCID: PMC10463201 DOI: 10.1182/bloodadvances.2022009618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 04/20/2023] [Accepted: 05/14/2023] [Indexed: 06/07/2023] Open
Abstract
Metabolic products of the microbiota can alter hematopoiesis. However, the contribution and site of action of bile acids is poorly understood. Here, we demonstrate that the secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA), increase bone marrow myelopoiesis. Treatment of bone marrow cells with DCA and LCA preferentially expanded immunophenotypic and functional colony-forming unit-granulocyte and macrophage (CFU-GM) granulocyte-monocyte progenitors (GMPs). DCA treatment of sorted hematopoietic stem and progenitor cells (HSPCs) increased CFU-GMs, indicating that direct exposure of HSPCs to DCA sufficed to increase GMPs. The vitamin D receptor (VDR) was required for the DCA-induced increase in CFU-GMs and GMPs. Single-cell RNA sequencing revealed that DCA significantly upregulated genes associated with myeloid differentiation and proliferation in GMPs. The action of DCA on HSPCs to expand GMPs in a VDR-dependent manner suggests microbiome-host interactions could directly affect bone marrow hematopoiesis and potentially the severity of infectious and inflammatory disease.
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Affiliation(s)
- Brandon Thompson
- Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA
| | - Shan Lu
- Department of Statistics, Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI
| | - Julio Revilla
- Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA
| | - Md Jashim Uddin
- Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA
| | - David N. Oakland
- Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA
| | - Savannah Brovero
- Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA
| | - Sunduz Keles
- Department of Statistics, Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI
| | - Emery H. Bresnick
- Wisconsin Blood Cancer Research Institute, Department of Cell and Regenerative Biology, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - William A. Petri
- Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA
| | - Stacey L. Burgess
- Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA
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18
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Mou Y, Bai X, Ma H, Li T, Zhao Y, Wu T, Zhang Y, Qu H, Kong H, Wang X, Zhao Y. Protective effect of carbon dots derived from scrambled Coptidis Rhizoma against ulcerative colitis in mice. Front Mol Biosci 2023; 10:1253195. [PMID: 37711388 PMCID: PMC10498776 DOI: 10.3389/fmolb.2023.1253195] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 08/17/2023] [Indexed: 09/16/2023] Open
Abstract
Introduction: Ulcerative colitis (UC) is a chronic and progressive inflammatory disease of the intestines. The primary symptoms, such as bloody diarrhea, can result in weight loss and significantly diminish the patient's quality of life. Despite considerable research endeavors, this disease remains incurable. The scrambled Coptidis Rhizoma (SCR) has a rich historical background in traditional Chinese medicine as a remedy for UC. Drawing from a wealth of substantial clinical practices, this study is focused on investigating the protective effects and underlying mechanisms of the active component of SCR, namely SCR-based carbon dots (SCR-CDs), in the treatment of UC. Methods: SCR-CDs were extracted and isolated from the decoction of SCR, followed by a comprehensive characterization of their morphological structure and functional groups. Subsequently, we investigated the effects of SCR-CDs on parameters such as colonic length, disease activity index, and histopathological architecture using the dextran sulfate sodium (DSS)-induced colitis mice model. Furthermore, we delved into the assessment of key aspects, including the expression of intestinal tight junction (TJ) proteins, inflammatory cytokines, oxidative stress markers, and gut microbial composition, to unravel the intricate mechanisms underpinning their therapeutic effects. Results: SCR-CDs displayed a consistent spherical morphology, featuring uniform dispersion and diameters ranging from 1.2 to 2.8 nm. These SCR-CDs also exhibited a diverse array of surface chemical functional groups. Importantly, the administration of SCR-CDs, particularly at higher dosage levels, exerted a noteworthy preventive influence on colonic shortening, elevation of the disease activity index and colonic tissue impairment caused by DSS. These observed effects may be closely associated with the hygroscopic capability and hemostatic bioactivity inherent to SCR-CDs. Concurrently, the application of SCR-CDs manifested an augmenting impact on the expression of intestinal TJ proteins, concomitantly leading to a significant reduction in inflammatory cell infiltration and amelioration of oxidative stress. Additionally, SCR-CDs treatment facilitated the restoration of perturbed gut microbial composition, potentially serving as a fundamental mechanism underlying their observed protective effects. Conclusion: This study demonstrates the significant therapeutic potential of SCR-CDs in UC and provides elucidation on some of their mechanisms. Furthermore, these findings hold paramount importance in guiding innovative drug discovery for anti-UC agents.
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Affiliation(s)
- Yanfang Mou
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xue Bai
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- Henan University of Chinese Medicine, Zhengzhou, China
| | - Huagen Ma
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Tingjie Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yafang Zhao
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Tong Wu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yue Zhang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Huihua Qu
- Center of Scientific Experiment, Beijing University of Chinese Medicine, Beijing, China
| | - Hui Kong
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xueqian Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yan Zhao
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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19
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Bénard A, Mittelstädt A, Klösch B, Glanz K, Müller J, Schoen J, Nüse B, Brunner M, Naschberger E, Stürzl M, Mattner J, Muñoz LE, Sohn K, Grützmann R, Weber GF. IL-3 orchestrates ulcerative colitis pathogenesis by controlling the development and the recruitment of splenic reservoir neutrophils. Cell Rep 2023; 42:112637. [PMID: 37300834 DOI: 10.1016/j.celrep.2023.112637] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 05/03/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) are a global health issue with an increasing incidence. Although the pathogenesis of IBDs has been investigated intensively, the etiology of IBDs remains enigmatic. Here, we report that interleukin-3 (Il-3)-deficient mice are more susceptible and exhibit increased intestinal inflammation during the early stage of experimental colitis. IL-3 is locally expressed in the colon by cells harboring a mesenchymal stem cell phenotype and protects by promoting the early recruitment of splenic neutrophils with high microbicidal capability into the colon. Mechanistically, IL-3-dependent neutrophil recruitment involves CCL5+ PD-1high LAG-3high T cells, STAT5, and CCL20 and is sustained by extramedullary splenic hematopoiesis. During acute colitis, Il-3-/- show, however, increased resistance to the disease as well as reduced intestinal inflammation. Altogether, this study deepens our understanding of IBD pathogenesis, identifies IL-3 as an orchestrator of intestinal inflammation, and reveals the spleen as an emergency reservoir for neutrophils during colonic inflammation.
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Affiliation(s)
- Alan Bénard
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
| | - Anke Mittelstädt
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Bettina Klösch
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Karolina Glanz
- Fraunhofer Institute for Interfacial Engineering and Biotechnology, Stuttgart, Germany
| | - Jan Müller
- Fraunhofer Institute for Interfacial Engineering and Biotechnology, Stuttgart, Germany
| | - Janina Schoen
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Björn Nüse
- Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU), Erlangen, Germany
| | - Maximilian Brunner
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Elisabeth Naschberger
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Michael Stürzl
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Jochen Mattner
- Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU), Erlangen, Germany
| | - Luis E Muñoz
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Kai Sohn
- Fraunhofer Institute for Interfacial Engineering and Biotechnology, Stuttgart, Germany
| | - Robert Grützmann
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Georg F Weber
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
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20
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Korta A, Kula J, Gomułka K. The Role of IL-23 in the Pathogenesis and Therapy of Inflammatory Bowel Disease. Int J Mol Sci 2023; 24:10172. [PMID: 37373318 DOI: 10.3390/ijms241210172] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/11/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Interleukin-23 (IL-23) is a proinflammatory cytokine produced mainly by macrophages and antigen-presenting cells (APCs) after antigenic stimulation. IL-23 plays a significant role as a mediator of tissue damage. Indeed, the irregularities in IL-23 and its receptor signaling have been implicated in inflammatory bowel disease. IL-23 interacts with both the innate and adaptive immune systems, and IL-23/Th17 appears to be involved in the development of chronic intestinal inflammation. The IL-23/Th17 axis may be a critical driver of this chronic inflammation. This review summarizes the main aspects of IL-23's biological function, cytokines that control cytokine production, effectors of the IL-23 response, and the molecular mechanisms associated with IBD pathogenesis. Although IL-23 modulates and impacts the development, course, and recurrence of the inflammatory response, the etiology and pathophysiology of IBD are not completely understood, but mechanism research shows huge potential for clinical applications as therapeutic targets in IBD treatment.
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Affiliation(s)
- Aleksandra Korta
- Student Scientific Group of Adult Allergology, Wroclaw Medical University, 50-369 Wroclaw, Poland
| | - Julia Kula
- Student Scientific Group of Adult Allergology, Wroclaw Medical University, 50-369 Wroclaw, Poland
| | - Krzysztof Gomułka
- Clinical Department of Internal Medicine, Pneumology and Allergology, Wroclaw Medical University, 50-369 Wroclaw, Poland
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21
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Kim Y, Kamada N. The role of the microbiota in myelopoiesis during homeostasis and inflammation. Int Immunol 2023; 35:267-274. [PMID: 36694400 PMCID: PMC10199171 DOI: 10.1093/intimm/dxad002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 01/23/2023] [Indexed: 01/26/2023] Open
Abstract
The microbiota engages in the development and maintenance of the host immune system. The microbiota affects not only mucosal tissues where it localizes but also the distal organs. Myeloid cells are essential for host defense as first responders of the host immune system. Their generation, called myelopoiesis, is regulated by environmental signals, including commensal microbiota. Hematopoietic stem and progenitor cells in bone marrow can directly or indirectly sense microbiota-derived signals, thereby giving rise to myeloid cell lineages at steady-state and during inflammation. In this review, we discuss the role of commensal microorganisms in the homeostatic regulation of myelopoiesis in the bone marrow. We also outline the effects of microbial signals on myelopoiesis during inflammation and infection, with a particular focus on the development of innate immune memory. Studying the relationship between the microbiota and myelopoiesis will help us understand how the microbiota regulates immune responses at a systemic level beyond the local mucosa.
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Affiliation(s)
- Yeji Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Nobuhiko Kamada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- Laboratory of Microbiology and Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan
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22
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Wang Y, Jin X, Li M, Gao J, Zhao X, Ma J, Shi C, He B, Hu L, Shi J, Liu G, Qu G, Zheng Y, Jiang G. PM 2.5 Increases Systemic Inflammatory Cells and Associated Disease Risks by Inducing NRF2-Dependent Myeloid-Biased Hematopoiesis in Adult Male Mice. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2023; 57:7924-7937. [PMID: 37184982 DOI: 10.1021/acs.est.2c09024] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
Although PM2.5 (fine particles with aerodynamic diameter <2.5 μm) exposure shows the potential to impact normal hematopoiesis, the detailed alterations in systemic hematopoiesis and the underlying mechanisms remain unclear. For hematopoiesis under steady-state or stress conditions, nuclear factor erythroid 2-related factor 2 (NRF2) is essential for regulating hematopoietic processes to maintain blood homeostasis. Herein, we characterized changes in the populations of hematopoietic stem progenitor cells and committed hematopoietic progenitors in the lungs and bone marrow (BM) of wild-type and Nrf2-/- C57BL/6J male mice. PM2.5-induced NRF2-dependent biased hematopoiesis toward myeloid lineage in the lungs and BM generates excessive numbers of various inflammatory immune cells, including neutrophils, monocytes, and platelets. The increased population of these immune cells in the lungs, BM, and peripheral blood has been associated with observed pulmonary fibrosis and high disease risks in an NRF2-dependent manner. Therefore, although NRF2 is a protective factor against stressors, upon PM2.5 exposure, NRF2 is involved in stress myelopoiesis and enhanced PM2.5 toxicity in pulmonary injury, even leading to systemic inflammation.
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Affiliation(s)
- Yuanyuan Wang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiaoting Jin
- School of Public Health, Qingdao University, Qingdao 266071, China
| | - Min Li
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- Research Center for Analytical Sciences, Department of Chemistry, College of Sciences, Northeastern University, Shenyang 110819, China
| | - Jie Gao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- School of Environmental, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310000, China
| | - Xingchen Zhao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Juan Ma
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chunzhen Shi
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- College of Ecology and Environment, Beijing Technology and Business University, Beijing 100048, China
| | - Bin He
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- School of Environmental, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310000, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ligang Hu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- School of Environmental, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310000, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
- Institute of Environment and Health, Jianghan University, Wuhan 430056, China
| | - Jianbo Shi
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- School of Environmental, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310000, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
- Institute of Environment and Health, Jianghan University, Wuhan 430056, China
| | - Guoliang Liu
- Department of Pulmonary and Critical Care Medicine, National Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China
- Institute of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, Chinese Academy of Medical Sciences, Beijing 100029, China
| | - Guangbo Qu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- School of Environmental, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310000, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
- Institute of Environment and Health, Jianghan University, Wuhan 430056, China
| | - Yuxin Zheng
- School of Public Health, Qingdao University, Qingdao 266071, China
| | - Guibin Jiang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- School of Environmental, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310000, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
- Institute of Environment and Health, Jianghan University, Wuhan 430056, China
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23
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Hegarty LM, Jones GR, Bain CC. Macrophages in intestinal homeostasis and inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2023:10.1038/s41575-023-00769-0. [PMID: 37069320 DOI: 10.1038/s41575-023-00769-0] [Citation(s) in RCA: 122] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/13/2023] [Indexed: 04/19/2023]
Abstract
Macrophages are essential for the maintenance of intestinal homeostasis, yet appear to be drivers of inflammation in the context of inflammatory bowel disease (IBD). How these peacekeepers become powerful aggressors in IBD is still unclear, but technological advances have revolutionized our understanding of many facets of their biology. In this Review, we discuss the progress made in understanding the heterogeneity of intestinal macrophages, the functions they perform in gut health and how the environment and origin can control the differentiation and longevity of these cells. We describe how these processes might change in the context of chronic inflammation and how aberrant macrophage behaviour contributes to IBD pathology, and discuss how therapeutic approaches might target dysregulated macrophages to dampen inflammation and promote mucosal healing. Finally, we set out key areas in the field of intestinal macrophage biology for which further investigation is warranted.
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Affiliation(s)
- Lizi M Hegarty
- Centre for Inflammation Research, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh BioQuarter, Queen's Medical Research Institute, Edinburgh, UK
| | - Gareth-Rhys Jones
- Centre for Inflammation Research, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh BioQuarter, Queen's Medical Research Institute, Edinburgh, UK
| | - Calum C Bain
- Centre for Inflammation Research, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh BioQuarter, Queen's Medical Research Institute, Edinburgh, UK.
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24
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Yan Y, Li K, Jiang J, Jiang L, Ma X, Ai F, Qiu S, Si W. Perinatal tissue-derived exosomes ameliorate colitis in mice by regulating the Foxp3 + Treg cells and gut microbiota. Stem Cell Res Ther 2023; 14:43. [PMID: 36941715 PMCID: PMC10029206 DOI: 10.1186/s13287-023-03263-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 03/06/2023] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND The capacity of self-renewal and multipotent differentiation makes mesenchymal stem cells (MSC) one of the most widely investigated cell lines in preclinical studies as cell-based therapies. However, the low survival rate and poor homing efficiency of MSCs after transplantation hinder the therapeutic application. Exosomes derived from MSCs have shown promising therapeutic potential in many diseases. However, the heterogeneity of MSCs may lead to differences in the function of secreting exosomes. In this study, the therapeutic effects of hUC-Exos and hFP-Exos on the DSS-induced colitis mouse model were investigated. METHODS The colitis mouse models were randomly divided into four groups: (1) DSS administered for 7 days and euthanasia (DSS7D), (2) DSS administered for 7 days and kept for another 7 days without any treatment (DSS14D), (3) DSS administered for 7 days and followed with hUC-EVs infusion for 7 days (hUC-EVs) and (4) DSS administered for 7 days and followed with hFP-EVs infusion for 7 days (hFP-EVs). We analyzed colon length, histopathology, Treg cells, cytokines and gut microbiota composition in each group. RESULTS A large amount of IL-6, IL-17 and IFN-γ were produced along with the decrease in the number of CD4 + Foxp3 + and CD8 + Foxp3 + cells in DSS7D group, which indicated that Th17 cells were activated and Treg cells were suppressed. We found that the number of CD4 + Foxp3 + and CD8 + Foxp3 + cells increased in order to suppress inflammation, but the length of colon did not recover and the symotoms were worsened of the colonic tissue in DSS14D group. The subsequent infusion of either hUC-Exos or hFP-Exos mediated the transformation of Treg and Th17 cells in colitis mice to maintain immune balance. The infusion of hUC-Exos and hFP-Exos also both reduced the abundance of pro-inflammatory intestinal bacterial such as Verrucomicrobia and Akkermansia muciniphila to improve colitis. CONCLUSIONS We found that Foxp3 + Treg cells can inhibit the inflammatory response, and the over-activated Treg cells can still further damage the intestinal mucosa. hUC-Exos and hFP-Exos can control inflammation by regulating the balance between Th17 cells and Treg cells. Decreased inflammatory response improved the structure of colon wall in mice and reduced the abundance of pro-inflammatory bacteria in the intestine. The improvement of intestinal wall structure provides conditions for the reproduction of beneficial bacteria, which further contributes to the reduction of colitis.
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Affiliation(s)
- Yaping Yan
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Kaixiu Li
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Jiang Jiang
- Department of Obstetrics, The First People's Hospital of Yunnan Province, Kunming, 650032, Yunnan, China
- Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
| | - Lihong Jiang
- Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
- Yunnan Key Laboratory of Innovative Application of Traditional Chinese Medicine, The First People's Hospital of Yunnan Province, Kunming, 650032, Yunnan, China
| | - Xiang Ma
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Fang Ai
- Department of Obstetrics, The First People's Hospital of Yunnan Province, Kunming, 650032, Yunnan, China
- Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
| | - Shuai Qiu
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Wei Si
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China.
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25
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Zhong D, Jiang H, Zhou C, Ahmed A, Li H, Wei X, Lian Q, Tastemel M, Xin H, Ge M, Zhang C, Jing L. The microbiota regulates hematopoietic stem and progenitor cell development by mediating inflammatory signals in the niche. Cell Rep 2023; 42:112116. [PMID: 36795566 DOI: 10.1016/j.celrep.2023.112116] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 12/23/2022] [Accepted: 01/27/2023] [Indexed: 02/17/2023] Open
Abstract
The commensal microbiota regulates the self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) in bone marrow. Whether and how the microbiota influences HSPC development during embryogenesis is unclear. Using gnotobiotic zebrafish, we show that the microbiota is necessary for HSPC development and differentiation. Individual bacterial strains differentially affect HSPC formation, independent of their effects on myeloid cells. Early-life dysbiosis in chd8-/- zebrafish impairs HSPC development. Wild-type microbiota promote HSPC development by controlling basal inflammatory cytokine expression in kidney niche, and chd8-/- commensals elicit elevated inflammatory cytokines that reduce HSPCs and enhance myeloid differentiation. We identify an Aeromonas veronii strain with immuno-modulatory activities that fails to induce HSPC development in wild-type fish but selectively inhibits kidney cytokine expression and rebalances HSPC development in chd8-/- zebrafish. Our studies highlight the important roles of a balanced microbiome during early HSPC development that ensure proper establishment of lineal precursor for adult hematopoietic system.
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Affiliation(s)
- Dan Zhong
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Shanghai Key Laboratory of Veterinary Biotechnology, Shanghai 200240, China
| | - Haowei Jiang
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Chengzhuo Zhou
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Abrar Ahmed
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Hongji Li
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Xiaona Wei
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Qiuyu Lian
- UM-SJTU Joint Institute, Department of Automation, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Melodi Tastemel
- Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Hongyi Xin
- Global Institute of Future Technology, Department of Automation, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Mei Ge
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Shanghai Laiyi Center for Biopharmaceutical R&D, Shanghai 200240, China
| | - Chenhong Zhang
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
| | - Lili Jing
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Shanghai Key Laboratory of Veterinary Biotechnology, Shanghai 200240, China.
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26
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Bai L, Dermadi D, Kalesinskas L, Dvorak M, Chang SE, Ganesan A, Rubin SJS, Kuo A, Cheung P, Donato M, Utz PJ, Habtezion A, Khatri P. Mass-cytometry-based quantitation of global histone post-translational modifications at single-cell resolution across peripheral immune cells in IBD. J Crohns Colitis 2022; 17:804-815. [PMID: 36571819 PMCID: PMC10155749 DOI: 10.1093/ecco-jcc/jjac194] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Indexed: 01/26/2023]
Abstract
BACKGROUND AND AIMS Current understanding of histone post-translational modifications (histone modifications) across immune cell types in patients with inflammatory bowel disease (IBD) during remission and flare is limited. The study aimed to quantify histone modifications at a single-cell resolution in IBD patients during remission and flare and how they differ compared to healthy controls. METHODS We performed a case-control study of 94 subjects (83 IBD patients and 11 healthy controls). IBD patients had either UC (n=38) or CD (n=45) in clinical remission or flare. We used epigenetic profiling by time-of-flight (EpiTOF) to investigate changes in histone modifications within peripheral blood mononuclear cells from IBD patients. RESULTS We discovered substantial heterogeneity in histone modifications across multiple immune cell types in IBD patients. They had a higher proportion of less differentiated CD34 + hematopoietic progenitors, and a subset of CD56 bright NK cells and γδ T cells characterized by distinct histone modifications associated with the gene transcription. The subset of CD56 bright NK cells had increased several histone acetylations. An epigenetically defined subset of NK was associated with higher levels of CRP in peripheral blood. CD14+ monocytes from IBD patients had significantly decreased cleaved H3T22, suggesting they were epigenetically primed for macrophage differentiation. CONCLUSION We describe the first systems-level quantification of histone modifications across immune cells from IBD patients at a single-cell resolution revealing the increased epigenetic heterogeneity that is not possible with traditional ChIP-seq profiling. Our data open new directions in investigating the association between histone modifications and IBD pathology using other epigenomic tools.
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Affiliation(s)
- Lawrence Bai
- Immunology Program, Stanford University School of Medicine, 1215 Welch Road, Modular B, Stanford, CA 94305 USA
| | - Denis Dermadi
- Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA 94305, USA.,Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA 94305, USA
| | - Laurynas Kalesinskas
- Biomedical Informatics Training Program, Stanford University School of Medicine, 1265 Welch Road, MSOB X-343, Stanford, CA 94305 USA
| | - Mai Dvorak
- Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA 94305, USA.,Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Sarah E Chang
- Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA 94305, USA.,Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Ananthakrishnan Ganesan
- Computational and Mathematical Engineering, Stanford University, 475 Via Ortega, Suite B060, Stanford, CA 94305 USA
| | - Samuel J S Rubin
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Alex Kuo
- Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA 94305, USA.,Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Peggie Cheung
- Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA 94305, USA.,Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Michele Donato
- Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA 94305, USA.,Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA 94305, USA
| | - Paul J Utz
- Immunology Program, Stanford University School of Medicine, 1215 Welch Road, Modular B, Stanford, CA 94305 USA.,Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA 94305, USA.,Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Aida Habtezion
- Immunology Program, Stanford University School of Medicine, 1215 Welch Road, Modular B, Stanford, CA 94305 USA.,Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA 94305, USA.,Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Purvesh Khatri
- Immunology Program, Stanford University School of Medicine, 1215 Welch Road, Modular B, Stanford, CA 94305 USA.,Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA 94305, USA.,Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA 94305, USA
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27
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Sezaki M, Hayashi Y, Nakato G, Wang Y, Nakata S, Biswas S, Morishima T, Fakruddin M, Moon J, Ahn S, Kim P, Miyamoto Y, Baba H, Fukuda S, Takizawa H. Hematopoietic stem and progenitor cells integrate microbial signals to promote post-inflammation gut tissue repair. EMBO J 2022; 41:e110712. [PMID: 36254590 PMCID: PMC9670188 DOI: 10.15252/embj.2022110712] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 09/09/2022] [Accepted: 09/16/2022] [Indexed: 01/13/2023] Open
Abstract
Bone marrow (BM)-resident hematopoietic stem and progenitor cells (HSPCs) are often activated following bacterial insults to replenish the host hemato-immune system, but how they integrate the associated tissue damage signals to initiate distal tissue repair is largely unknown. Here, we show that acute gut inflammation expands HSPCs in the BM and directs them to inflamed mesenteric lymph nodes through GM-CSFR activation for further expansion and potential differentiation into Ly6C+ /G+ myeloid cells specialized in gut tissue repair. We identified this process to be mediated by Bacteroides, a commensal gram-negative bacteria that activates innate immune signaling. These findings establish cross-organ communication between the BM and distant inflamed sites, whereby a certain subset of multipotent progenitors is specified to respond to imminent hematopoietic demands and to alleviate inflammatory symptoms.
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Affiliation(s)
- Maiko Sezaki
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
- Laboratory of Hematopoietic Stem Cell Engineering, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
| | - Yoshikazu Hayashi
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
- Laboratory of Hematopoietic Stem Cell Engineering, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
- Division of Functional Structure, Department of Morphological BiologyFukuoka Dental CollegeFukuokaJapan
| | - Gaku Nakato
- Gut Environmental Design GroupKanagawa Institute of Industrial Science and TechnologyKawasakiJapan
| | - Yuxin Wang
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
- Department of Hematology, Zhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Sayuri Nakata
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
| | - Subinoy Biswas
- Department of ImmunologyUniversity of PittsburghPittsburghPAUSA
| | - Tatsuya Morishima
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
- Laboratory of Hematopoietic Stem Cell Engineering, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
| | - Md Fakruddin
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
| | - Jieun Moon
- Graduate School of Nanoscience and TechnologyKorea Advanced Institute of Science and Technology (KAIST)DaejeonRepublic of Korea
| | - Soyeon Ahn
- Graduate School of Nanoscience and TechnologyKorea Advanced Institute of Science and Technology (KAIST)DaejeonRepublic of Korea
| | - Pilhan Kim
- Graduate School of Nanoscience and TechnologyKorea Advanced Institute of Science and Technology (KAIST)DaejeonRepublic of Korea
- Graduate School of Medical Science and EngineeringKorea Advanced Institute of Science and Technology (KAIST)DaejeonRepublic of Korea
| | - Yuji Miyamoto
- Department of Gastroenterological Surgery, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
- Center for Metabolic Regulation of Healthy AgingKumamoto UniversityKumamotoJapan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
- Center for Metabolic Regulation of Healthy AgingKumamoto UniversityKumamotoJapan
| | - Shinji Fukuda
- Gut Environmental Design GroupKanagawa Institute of Industrial Science and TechnologyKawasakiJapan
- Institute for Advanced BiosciencesKeio UniversityYamagata‐TsuruokaJapan
- Transborder Medical Research CenterUniversity of TsukubaTsukubaJapan
- Laboratory for Regenerative MicrobiologyJuntendo University Graduate School of MedicineTokyoJapan
| | - Hitoshi Takizawa
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
- Center for Metabolic Regulation of Healthy AgingKumamoto UniversityKumamotoJapan
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28
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Wang Y, Li M, Wang S, Ma J, Liu Y, Guo H, Gao J, Yao L, He B, Hu L, Qu G, Jiang G. Deciphering the Effects of 2D Black Phosphorus on Disrupted Hematopoiesis and Pulmonary Immune Homeostasis Using a Developed Flow Cytometry Method. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2022; 56:15869-15881. [PMID: 36227752 PMCID: PMC9671123 DOI: 10.1021/acs.est.2c03675] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 09/25/2022] [Accepted: 09/27/2022] [Indexed: 05/28/2023]
Abstract
As an emerging two-dimensional nanomaterial with promising prospects, mono- or few-layer black phosphorus (BP) is potentially toxic to humans. We investigated the effects of two types of BPs on adult male mice through intratracheal instillation. Using the flow cytometry method, the generation, migration, and recruitment of immune cells in different organs have been characterized on days 1, 7, 14, and 21 post-exposure. Compared with small BP (S-BP, lateral size at ∼188 nm), large BP (L-BP, lateral size at ∼326 nm) induced a stronger stress lymphopoiesis and B cell infiltration into the alveolar sac. More importantly, L-BP dramatically increased peripheral neutrophil (NE) counts up to 1.9-fold on day 21 post-exposure. Decreased expression of the CXCR4 on NEs, an important regulator of NE retention in the bone marrow, explained the increased NE release into the circulation induced by L-BP. Therefore, BP triggers systemic inflammation via the disruption of both the generation and migration of inflammatory immune cells.
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Affiliation(s)
- Yuanyuan Wang
- State
Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese
Academy of Sciences, Beijing 100085, China
- College
of Resources and Environment, University
of Chinese Academy of Sciences, Beijing 100049, China
| | - Min Li
- State
Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese
Academy of Sciences, Beijing 100085, China
- Research
Center for Analytical Sciences, Department of Chemistry, College of
Sciences, Northeastern University, Shenyang 110819, China
| | - Shunhao Wang
- State
Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese
Academy of Sciences, Beijing 100085, China
- College
of Resources and Environment, University
of Chinese Academy of Sciences, Beijing 100049, China
| | - Junjie Ma
- State
Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese
Academy of Sciences, Beijing 100085, China
- Research
Center for Analytical Sciences, Department of Chemistry, College of
Sciences, Northeastern University, Shenyang 110819, China
| | - Yaquan Liu
- State
Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese
Academy of Sciences, Beijing 100085, China
- College
of Resources and Environment, University
of Chinese Academy of Sciences, Beijing 100049, China
| | - Hao Guo
- State
Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese
Academy of Sciences, Beijing 100085, China
- College
of Resources and Environment, University
of Chinese Academy of Sciences, Beijing 100049, China
| | - Jie Gao
- School
of Environmental, Hangzhou Institute for
Advanced Study, UCAS, Hangzhou 310000, China
| | - Linlin Yao
- State
Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese
Academy of Sciences, Beijing 100085, China
| | - Bin He
- State
Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese
Academy of Sciences, Beijing 100085, China
- School
of Environmental, Hangzhou Institute for
Advanced Study, UCAS, Hangzhou 310000, China
- College
of Resources and Environment, University
of Chinese Academy of Sciences, Beijing 100049, China
| | - Ligang Hu
- State
Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese
Academy of Sciences, Beijing 100085, China
- School
of Environmental, Hangzhou Institute for
Advanced Study, UCAS, Hangzhou 310000, China
- College
of Resources and Environment, University
of Chinese Academy of Sciences, Beijing 100049, China
- Institute
of Environment and Health, Jianghan University, Wuhan 430056, China
| | - Guangbo Qu
- State
Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese
Academy of Sciences, Beijing 100085, China
- School
of Environmental, Hangzhou Institute for
Advanced Study, UCAS, Hangzhou 310000, China
- College
of Resources and Environment, University
of Chinese Academy of Sciences, Beijing 100049, China
- Institute
of Environment and Health, Jianghan University, Wuhan 430056, China
| | - Guibin Jiang
- State
Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese
Academy of Sciences, Beijing 100085, China
- School
of Environmental, Hangzhou Institute for
Advanced Study, UCAS, Hangzhou 310000, China
- College
of Resources and Environment, University
of Chinese Academy of Sciences, Beijing 100049, China
- Institute
of Environment and Health, Jianghan University, Wuhan 430056, China
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29
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Urao N, Liu J, Takahashi K, Ganesh G. Hematopoietic Stem Cells in Wound Healing Response. Adv Wound Care (New Rochelle) 2022; 11:598-621. [PMID: 34353116 PMCID: PMC9419985 DOI: 10.1089/wound.2021.0065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Significance: Emerging evidence has shown a link between the status of hematopoietic stem cells (HSCs) and wound healing responses. Thus, better understanding HSCs will contribute to further advances in wound healing research. Recent Advances: Myeloid cells such as neutrophils and monocyte-derived macrophages are critical players in the process of wound healing. HSCs actively respond to wound injury and other tissue insults, including infection and produce the effector myeloid cells, and a failing of the HSC response can result in impaired wound healing. Technological advances such as transcriptome at single-cell resolution, epigenetics, three-dimensional imaging, transgenic animals, and animal models, have provided novel concepts of myeloid generation (myelopoiesis) from HSCs, and have revealed cell-intrinsic and -extrinsic mechanisms that can impact HSC functions in the context of health conditions. Critical Issues: The newer concepts include-the programmed cellular fate at a differentiation stage that is used to be considered as the multilineage, the signaling pathways that can activate HSCs directly and indirectly, the mechanisms that can deteriorate HSCs, the roles and remodeling of the surrounding environment for HSCs and their progenitors (the niche). Future Directions: The researches on HSCs, which produce blood cells, should contribute to the development of blood biomarkers predicting a risk of chronic wounds, which may transform clinical practice of wound care with precision medicine for patients at high risk of poor healing.
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Affiliation(s)
- Norifumi Urao
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York, USA.,Correspondence: Department of Pharmacology, State University of New York Upstate Medical University, 766 Irving Avenue, Weiskotten Hall Room 5322, Syracuse, NY 13210, USA.
| | - Jinghua Liu
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York, USA
| | - Kentaro Takahashi
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York, USA
| | - Gayathri Ganesh
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York, USA
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30
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Mende N, Bastos HP, Santoro A, Mahbubani KT, Ciaurro V, Calderbank EF, Londoño MQ, Sham K, Mantica G, Morishima T, Mitchell E, Lidonnici MR, Meier-Abt F, Hayler D, Jardine L, Curd A, Haniffa M, Ferrari G, Takizawa H, Wilson NK, Göttgens B, Saeb-Parsy K, Frontini M, Laurenti E. Unique molecular and functional features of extramedullary hematopoietic stem and progenitor cell reservoirs in humans. Blood 2022; 139:3387-3401. [PMID: 35073399 PMCID: PMC7612845 DOI: 10.1182/blood.2021013450] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 01/05/2022] [Indexed: 02/02/2023] Open
Abstract
Rare hematopoietic stem and progenitor cell (HSPC) pools outside the bone marrow (BM) contribute to blood production in stress and disease but remain ill-defined. Although nonmobilized peripheral blood (PB) is routinely sampled for clinical management, the diagnosis and monitoring potential of PB HSPCs remain untapped, as no healthy PB HSPC baseline has been reported. Here we comprehensively delineate human extramedullary HSPC compartments comparing spleen, PB, and mobilized PB to BM using single-cell RNA-sequencing and/or functional assays. We uncovered HSPC features shared by extramedullary tissues and others unique to PB. First, in contrast to actively dividing BM HSPCs, we found no evidence of substantial ongoing hematopoiesis in extramedullary tissues at steady state but report increased splenic HSPC proliferative output during stress erythropoiesis. Second, extramedullary hematopoietic stem cells/multipotent progenitors (HSCs/MPPs) from spleen, PB, and mobilized PB share a common transcriptional signature and increased abundance of lineage-primed subsets compared with BM. Third, healthy PB HSPCs display a unique bias toward erythroid-megakaryocytic differentiation. At the HSC/MPP level, this is functionally imparted by a subset of phenotypic CD71+ HSCs/MPPs, exclusively producing erythrocytes and megakaryocytes, highly abundant in PB but rare in other adult tissues. Finally, the unique erythroid-megakaryocytic-skewing of PB is perturbed with age in essential thrombocythemia and β-thalassemia. Collectively, we identify extramedullary lineage-primed HSPC reservoirs that are nonproliferative in situ and report involvement of splenic HSPCs during demand-adapted hematopoiesis. Our data also establish aberrant composition and function of circulating HSPCs as potential clinical indicators of BM dysfunction.
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Affiliation(s)
- Nicole Mende
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Hugo P. Bastos
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Antonella Santoro
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Krishnaa T. Mahbubani
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Department of Haematology and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, UK
| | - Valerio Ciaurro
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Emily F. Calderbank
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Mariana Quiroga Londoño
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Kendig Sham
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Giovanna Mantica
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Tatsuya Morishima
- Laboratory of Stem Cell Stress, International Research Centre for Medical Sciences, and Centre for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto, Japan
- Laboratory of Hematopoietic Stem Cell Engineering, International Research Center for Medical Sciences, Kumamoto University, 860-0811 Kumamoto, Japan
| | - Emily Mitchell
- Cancer, Ageing and Somatic Mutation Group, Wellcome Sanger Institute, Hinxton, UK
| | - Maria Rosa Lidonnici
- San Raffaele-Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Fabienne Meier-Abt
- Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
- Institute of Molecular Systems Biology (IMSB), ETH Zurich, Zurich, Switzerland
- Institute of Medical Genetics, University of Zurich, Zurich, Switzerland
| | - Daniel Hayler
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Laura Jardine
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
- Haematology Department, Freeman Hospital, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, NE7 7DN, UK
| | - Abbie Curd
- Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, UK
| | - Muzlifah Haniffa
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
- Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE2 4LP, UK
| | - Giuliana Ferrari
- San Raffaele-Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Hitoshi Takizawa
- Laboratory of Stem Cell Stress, International Research Centre for Medical Sciences, and Centre for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto, Japan
| | - Nicola K. Wilson
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Berthold Göttgens
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Kourosh Saeb-Parsy
- Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, UK
| | - Mattia Frontini
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Institute of Biomedical & Clinical Science, College of Medicine and Health, University of Exeter Medical School, Exeter, UK
- National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom
- British Heart Foundation Centre of Excellence, Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - Elisa Laurenti
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
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31
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New Targets for Antiviral Therapy: Inhibitory Receptors and Immune Checkpoints on Myeloid Cells. Viruses 2022; 14:v14061144. [PMID: 35746616 PMCID: PMC9230063 DOI: 10.3390/v14061144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 05/23/2022] [Indexed: 11/26/2022] Open
Abstract
Immune homeostasis is achieved by balancing the activating and inhibitory signal transduction pathways mediated via cell surface receptors. Activation allows the host to mount an immune response to endogenous and exogenous antigens; suppressive modulation via inhibitory signaling protects the host from excessive inflammatory damage. The checkpoint regulation of myeloid cells during immune homeostasis raised their profile as important cellular targets for treating allergy, cancer and infectious disease. This review focuses on the structure and signaling of inhibitory receptors on myeloid cells, with particular attention placed on how the interplay between viruses and these receptors regulates antiviral immunity. The status of targeting inhibitory receptors on myeloid cells as a new therapeutic approach for antiviral treatment will be analyzed.
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32
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Abstract
The interleukin-23 [IL-23] cytokine, derived predominantly from macrophages and dendritic cells in response to microbial stimulation, has emerged as a critical promoter of chronic intestinal inflammation. Genome-wide association studies linking variants in IL23R to disease protection, bolstered by experimental evidence from colitis models, and the successful application of therapies against the IL-12/IL-23 shared p40 subunit in the treatment of inflammatory bowel disease [IBD] all provide compelling evidence of a crucial role for IL-23 in disease pathogenesis. Moreover, targeting the p19 subunit specific for IL-23 has shown considerable promise in recent phase 2 studies in IBD. The relative importance of the diverse immunological pathways downstream of IL-23 in propagating mucosal inflammation in the gut, however, remains contentious. Here we review current understanding of IL-23 biology and explore its pleiotropic effects on T cells, and innate lymphoid, myeloid and intestinal epithelial cells in the context of the pathogenesis of IBD. We furthermore discuss these pathways in the light of recent evidence from clinical trials and indicate emerging targets amenable to therapeutic intervention and translation into clinical practice.
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Affiliation(s)
- Gavin W Sewell
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
| | - Arthur Kaser
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
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33
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Vaillant L, Oster P, McMillan B, Orozco Fernandez E, Velin D. GM-CSF is key in the efficacy of vaccine-induced reduction of Helicobacter pylori infection. Helicobacter 2022; 27:e12875. [PMID: 35092634 PMCID: PMC9285700 DOI: 10.1111/hel.12875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 11/22/2021] [Accepted: 01/16/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Helicobacter pylori (H. pylori) colonizes the human gastric mucosa with a high worldwide prevalence. Currently, H. pylori is eradicated by the use of antibiotics. However, elevated antibiotic resistance suggests new therapeutic strategies need to be envisioned: one approach being prophylactic vaccination. Pre-clinical and clinical data show that a urease-based vaccine is efficient in decreasing H. pylori infection through the mobilization of T helper (Th) cells, especially Th17 cells. Th17 cells produce interleukins such as IL-22 and IL-17, among others, and are key players in vaccine efficacy. Recently, granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing Th17 cells have been identified. AIM This study explores the possibility that GM-CSF plays a role in the reduction of H. pylori infection following vaccination. RESULTS We demonstrate that GM-CSF+ IL-17+ Th17 cells accumulate in the stomach mucosa of H. pylori infected mice during the vaccine-induced reduction of H. pylori infection. Secondly, we provide evidence that vaccinated GM-CSF deficient mice only modestly reduce H. pylori infection. Conversely, we observe that an increase in GM-CSF availability reduces H. pylori burden in chronically infected mice. Thirdly, we show that GM-CSF, by acting on gastric epithelial cells, promotes the production of βdefensin3, which exhibits H. pylori bactericidal activities. CONCLUSION Taken together, we demonstrate a key role of GM-CSF, most probably originating from Th17 cells, in the vaccine-induced reduction of H. pylori infection.
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Affiliation(s)
- Laurie Vaillant
- Service of Gastroenterology and HepatologyCentre Hospitalier Universitaire VaudoisUniversity of LausanneLausanneSwitzerland
| | - Paul Oster
- Service of Gastroenterology and HepatologyCentre Hospitalier Universitaire VaudoisUniversity of LausanneLausanneSwitzerland
| | - Brynn McMillan
- Service of Gastroenterology and HepatologyCentre Hospitalier Universitaire VaudoisUniversity of LausanneLausanneSwitzerland
| | - Eulalia Orozco Fernandez
- Service of Gastroenterology and HepatologyCentre Hospitalier Universitaire VaudoisUniversity of LausanneLausanneSwitzerland
| | - Dominique Velin
- Service of Gastroenterology and HepatologyCentre Hospitalier Universitaire VaudoisUniversity of LausanneLausanneSwitzerland
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34
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Effects of oral wound on the neutrophil lineage in murine bone-marrow: Modulation mechanism hindered by chlorhexidine. Int Immunopharmacol 2022; 105:108544. [DOI: 10.1016/j.intimp.2022.108544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 11/18/2022]
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35
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Marins-Dos-Santos A, Ayres-Silva JDP, Antunes D, Moreira CJDC, Pelajo-Machado M, Alfaro D, Zapata AG, Bonomo AC, Savino W, de Meis J, Farias-de-Oliveira DA. Oral Trypanosoma cruzi Acute Infection in Mice Targets Primary Lymphoid Organs and Triggers Extramedullary Hematopoiesis. Front Cell Infect Microbiol 2022; 12:800395. [PMID: 35402296 PMCID: PMC8990980 DOI: 10.3389/fcimb.2022.800395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 02/24/2022] [Indexed: 12/03/2022] Open
Abstract
During the acute phase of Chagas disease, Trypanosoma cruzi circulation through the bloodstream leads to high tissue parasitism in the host. In primary lymphoid organs, progenitor cell reduction paralleled transient immunosuppression. Herein we showed that acute oral infection in mice promotes diffuse parasitism in bone marrow cells at 14 and 21 days post-infection (dpi), with perivascular regions, intravascular regions, and regions near the bone being target sites of parasite replication. Phenotypic analysis of hematopoietic differentiation in the bone marrow of infected mice showed that the cell number in the tissue is decreased (lineage-negative and lineage-positive cells). Interestingly, analysis of hematopoietic branching points showed that hematopoietic stem and progenitor cells (HSPCs) were significantly increased at 14 dpi. In addition, the pool of progenitors with stem plasticity (HSC-MPP3), as well as multipotent progenitors (MPPs) such as MPP4, also showed this pattern of increase. In contrast, subsequent progenitors that arise from MPPs, such as common lymphoid progenitors (CLPs), lymphoid-primed MPPs (LMPPs), and myeloid progenitors, were not enhanced; conversely, all presented numeric decline. Annexin V staining revealed that cell death increase in the initial hematopoietic branching point probably is not linked to CLPs and that myeloid progenitors decreased at 14 and 21 dpi. In parallel, our investigation provided clues that myeloid progenitor decrease could be associated with an atypical expression of Sca-1 in this population leading to a remarkable increase on LSK-like cells at 14 dpi within the HSPC compartment. Finally, these results led us to investigate HSPC presence in the spleen as a phenomenon triggered during emergency hematopoiesis due to mobilization or expansion of these cells in extramedullary sites. Splenocyte analysis showed a progressive increase in HSPCs between 14 and 21 dpi. Altogether, our study shows that the bone marrow is a target tissue in T. cruzi orally infected mice, leading to a hematopoietic disturbance with LSK-like cell bias accounting on HSPCs possibly affecting myeloid progenitor numbers. The LMPP and CLP reduction converges with defective thymocyte development. Lastly, it is tempting to speculate that the extramedullary hematopoiesis seen in the spleen is a mechanism involved in the hematological maintenance reported during the acute phase of oral T. cruzi infection.
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Affiliation(s)
- Alessandro Marins-Dos-Santos
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Brazilian National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | | | - Dina Antunes
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Brazilian National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | | | - Marcelo Pelajo-Machado
- Brazilian National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Laboratory of Pathology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - David Alfaro
- Department of Cell Biology, Faculty of Biology, Complutense University of Madrid, Madrid, Spain
| | - Agustín G. Zapata
- Department of Cell Biology, Faculty of Biology, Complutense University of Madrid, Madrid, Spain
| | - Adriana Cesar Bonomo
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Brazilian National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Rio de Janeiro Research Network on Neuroinflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Wilson Savino
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Brazilian National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Rio de Janeiro Research Network on Neuroinflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- *Correspondence: Wilson Savino, ; ; Désio Aurélio Farias-de-Oliveira, ;
| | - Juliana de Meis
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Brazilian National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Rio de Janeiro Research Network on Neuroinflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Désio Aurélio Farias-de-Oliveira
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Brazilian National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Rio de Janeiro Research Network on Neuroinflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- *Correspondence: Wilson Savino, ; ; Désio Aurélio Farias-de-Oliveira, ;
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Petruzzelli M, Ferrer M, Schuijs MJ, Kleeman SO, Mourikis N, Hall Z, Perera D, Raghunathan S, Vacca M, Gaude E, Lukey MJ, Jodrell DI, Frezza C, Wagner EF, Venkitaraman AR, Halim TYF, Janowitz T. Early Neutrophilia Marked by Aerobic Glycolysis Sustains Host Metabolism and Delays Cancer Cachexia. Cancers (Basel) 2022; 14:963. [PMID: 35205709 PMCID: PMC8870098 DOI: 10.3390/cancers14040963] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 02/09/2022] [Accepted: 02/09/2022] [Indexed: 02/01/2023] Open
Abstract
An elevated neutrophil-lymphocyte ratio negatively predicts the outcome of patients with cancer and is associated with cachexia, the terminal wasting syndrome. Here, using murine model systems of colorectal and pancreatic cancer we show that neutrophilia in the circulation and multiple organs, accompanied by extramedullary hematopoiesis, is an early event during cancer progression. Transcriptomic and metabolic assessment reveals that neutrophils in tumor-bearing animals utilize aerobic glycolysis, similar to cancer cells. Although pharmacological inhibition of aerobic glycolysis slows down tumor growth in C26 tumor-bearing mice, it precipitates cachexia, thereby shortening the overall survival. This negative effect may be explained by our observation that acute depletion of neutrophils in pre-cachectic mice impairs systemic glucose homeostasis secondary to altered hepatic lipid processing. Thus, changes in neutrophil number, distribution, and metabolism play an adaptive role in host metabolic homeostasis during cancer progression. Our findings provide insight into early events during cancer progression to cachexia, with implications for therapy.
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Affiliation(s)
- Michele Petruzzelli
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; (M.P.); (M.F.); (D.P.); (E.G.); (C.F.)
| | - Miriam Ferrer
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; (M.P.); (M.F.); (D.P.); (E.G.); (C.F.)
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; (S.O.K.); (N.M.); (M.J.L.)
| | - Martijn J. Schuijs
- CRUK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Cambridge CB2 0RE, UK; (M.J.S.); (S.R.); (D.I.J.); (T.Y.F.H.)
| | - Sam O. Kleeman
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; (S.O.K.); (N.M.); (M.J.L.)
| | - Nicholas Mourikis
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; (S.O.K.); (N.M.); (M.J.L.)
| | - Zoe Hall
- Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK;
| | - David Perera
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; (M.P.); (M.F.); (D.P.); (E.G.); (C.F.)
| | - Shwethaa Raghunathan
- CRUK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Cambridge CB2 0RE, UK; (M.J.S.); (S.R.); (D.I.J.); (T.Y.F.H.)
| | - Michele Vacca
- Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK;
| | - Edoardo Gaude
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; (M.P.); (M.F.); (D.P.); (E.G.); (C.F.)
| | - Michael J. Lukey
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; (S.O.K.); (N.M.); (M.J.L.)
| | - Duncan I. Jodrell
- CRUK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Cambridge CB2 0RE, UK; (M.J.S.); (S.R.); (D.I.J.); (T.Y.F.H.)
| | - Christian Frezza
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; (M.P.); (M.F.); (D.P.); (E.G.); (C.F.)
| | - Erwin F. Wagner
- Laboratory Genes and Disease, Department of Laboratory Medicine Department of Dermatology, Medical University of Vienna (MUV), 1090 Vienna, Austria;
- Laboratory Genes and Disease, Department of Dermatology, Medical University of Vienna (MUV), 1090 Vienna, Austria
| | - Ashok R. Venkitaraman
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; (M.P.); (M.F.); (D.P.); (E.G.); (C.F.)
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
- Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
| | - Timotheus Y. F. Halim
- CRUK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Cambridge CB2 0RE, UK; (M.J.S.); (S.R.); (D.I.J.); (T.Y.F.H.)
| | - Tobias Janowitz
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; (S.O.K.); (N.M.); (M.J.L.)
- Northwell Health Cancer Institute, New Hyde Park, NY 11042, USA
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37
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Das A, Harly C, Ding Y, Bhandoola A. ILC Differentiation from Progenitors in the Bone Marrow. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1365:7-24. [DOI: 10.1007/978-981-16-8387-9_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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38
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Bono C, Guerrero P, Jordán-Pla A, Erades A, Salomonis N, Grimes HL, Gil ML, Yáñez A. GM-CSF Programs Hematopoietic Stem and Progenitor Cells During Candida albicans Vaccination for Protection Against Reinfection. Front Immunol 2021; 12:790309. [PMID: 34975887 PMCID: PMC8715000 DOI: 10.3389/fimmu.2021.790309] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 11/25/2021] [Indexed: 11/19/2022] Open
Abstract
More mechanistic studies are needed to reveal the hidden details of in vivo-induced trained immunity. Here, using a Candida albicans live vaccine mouse model we show that vaccination protects mice against a secondary infection and increases the number of bone marrow, and especially, splenic trained monocytes. Moreover, vaccination expands and reprograms hematopoietic stem and progenitor cells (HSPCs) early during infection and mobilize them transiently to the spleen to produce trained macrophages. Trained HSPCs are not only primed for myeloid cell production but also reprogramed to produce a greater amount of proinflammatory cytokines in response to a second challenge. Additionally, their adoptive transfer is sufficient to protect mice against reinfection. Mechanistically, autocrine GM-CSF activation of HSPCs is responsible for the trained phenotype and essential for the vaccine-induced protection. Our findings reveal a fundamental role for HSPCs in the trained immune protective response, opening new avenues for disease prevention and treatment.
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Affiliation(s)
- Cristina Bono
- Departamento de Microbiología y Ecología, Facultad de Ciencias Biológicas, Instituto de Biotecnología y Biomedicina (BIOTECMED), Universitat de València, Burjassot, Spain
| | - Paula Guerrero
- Departamento de Microbiología y Ecología, Facultad de Ciencias Biológicas, Instituto de Biotecnología y Biomedicina (BIOTECMED), Universitat de València, Burjassot, Spain
| | - Antonio Jordán-Pla
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Facultad de Ciencias Biológicas, Instituto de Biotecnología y Biomedicina (BIOTECMED), Universitat de València, Burjassot, Spain
| | - Ana Erades
- Departamento de Microbiología y Ecología, Facultad de Ciencias Biológicas, Instituto de Biotecnología y Biomedicina (BIOTECMED), Universitat de València, Burjassot, Spain
| | - Nathan Salomonis
- Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - H. Leighton Grimes
- Division of Immunobiology and Center for Systems Immunology and Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - M. Luisa Gil
- Departamento de Microbiología y Ecología, Facultad de Ciencias Biológicas, Instituto de Biotecnología y Biomedicina (BIOTECMED), Universitat de València, Burjassot, Spain
| | - Alberto Yáñez
- Departamento de Microbiología y Ecología, Facultad de Ciencias Biológicas, Instituto de Biotecnología y Biomedicina (BIOTECMED), Universitat de València, Burjassot, Spain
- *Correspondence: Alberto Yáñez,
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Abstract
Granulocyte macrophage-colony stimulating factor (GM-CSF) was originally identified as a growth factor for its ability to promote the proliferation and differentiation in vitro of bone marrow progenitor cells into granulocytes and macrophages. Many preclinical studies, using GM-CSF deletion or depletion approaches, have demonstrated that GM-CSF has a wide range of biological functions, including the mediation of inflammation and pain, indicating that it can be a potential target in many inflammatory and autoimmune conditions. This review provides a brief overview of GM-CSF biology and signaling, and summarizes the findings from preclinical models of a range of inflammatory and autoimmune disorders and the latest clinical trials targeting GM-CSF or its receptor in these disorders.
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Affiliation(s)
- Adrian A Achuthan
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria 3050, Australia.
| | - Kevin M C Lee
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria 3050, Australia
| | - John A Hamilton
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria 3050, Australia; Australian Institute for Musculoskeletal Science, St Albans, Victoria 3021, Australia
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40
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Ingelfinger F, De Feo D, Becher B. GM-CSF: Master regulator of the T cell-phagocyte interface during inflammation. Semin Immunol 2021; 54:101518. [PMID: 34763973 DOI: 10.1016/j.smim.2021.101518] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 10/23/2021] [Indexed: 12/21/2022]
Abstract
The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) was sequentially redefined during the past decades. Originally described as a hematopoietic growth factor for myelopoiesis, GM-CSF was recognized as a central mediator of inflammation bridging the innate and adaptive arms of the immune system. Phagocytes sensing GM-CSF adapt an inflammatory phenotype and facilitate pathogen clearance. However, in the context of chronic tissue inflammation, GM-CSF secreted by tissue-invading lymphocytes has detrimental effects by licensing tissue damage and hyperinflammation. Accordingly, therapeutic intervention at the T cell-phagocyte interface represents an attractive target to ameliorate disease progression and immunopathology. Although GM-CSF is largely dispensable for steady state myelopoiesis, dysregulation, as seen in chronic inflammatory diseases, may however lead to disrupted haematopoiesis and long-term effects on bone marrow output. Here, we will survey the role of GM-CSF during inflammation, discuss the extent to which GM-CSF-secreting T cells, debate their introduction as a separate T cell lineage and explore current and future clinical implications of GM-CSF in human disease settings.
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Affiliation(s)
- Florian Ingelfinger
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland; Department of Neurology, University Hospital Zurich, Zurich, Switzerland
| | - Donatella De Feo
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Burkhard Becher
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
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41
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Mende N, Laurenti E. Hematopoietic stem and progenitor cells outside the bone marrow: where, when, and why. Exp Hematol 2021; 104:9-16. [PMID: 34687807 DOI: 10.1016/j.exphem.2021.10.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/06/2021] [Accepted: 10/08/2021] [Indexed: 12/23/2022]
Abstract
Bone marrow (BM) is the primary site of adult blood production, hosting the majority of all hematopoietic stem and progenitor cells (HSPCs). Rare HSPCs are also found outside of the BM at steady state. In times of large hematopoietic demand or BM failure, substantial production of mature blood cells from HSPCs can occur in a number of tissues, in a process termed extramedullary hematopoiesis (EMH). Over the past decades, our understanding of BM hematopoiesis has advanced drastically. In contrast there has been very little focus on the study of extramedullary HSPC pools and their contributions to blood production. Here we summarize what is currently known about extramedullary HSPCs and EMH in mice and humans. We describe the evidence of existing extramedullary HSPC pools at steady state, then discuss their role in the hematopoietic stress response. We highlight that although EMH in humans is much less pronounced and likely physiologically distinct to that in mice, it can be informative about premalignant and malignant changes. Finally, we reflect on the open questions in the field and on whether a better understanding of EMH, particularly in humans, may have relevant clinical implications for hematological and nonhematological disorders.
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Affiliation(s)
- Nicole Mende
- Department of Haematology and Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Elisa Laurenti
- Department of Haematology and Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
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42
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Patrolling human SLE haematopoietic progenitors demonstrate enhanced extramedullary colonisation; implications for peripheral tissue injury. Sci Rep 2021; 11:15759. [PMID: 34344937 PMCID: PMC8333421 DOI: 10.1038/s41598-021-95224-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 07/06/2021] [Indexed: 12/28/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease where bone-marrow-derived haematopoietic cells have a key role in its pathogenesis with accumulating evidence suggesting an aberrant function of haematopoietic stem/progenitor cells (HSPCs). We examined whether patrolling HSPCs differ from bone-marrow HSPCs both in SLE and healthy individuals, and how they participate in peripheral tissue injury. By employing next-generation RNA sequencing, the transcriptomes of CD34+ HSPCs deriving from the bone marrow and those patrolling the bloodstream of both healthy and individuals with SLE were compared. Patrolling SLE and Healthy human HSPC kinetics were examined through their inoculation into humanised mice. Patrolling and bone-marrow HSPCs have distinct molecular signatures, while patrolling SLE HSPCs showed an enhanced extramedullary gene expression profile. Non-mobilised, SLE-derived circulating HSPCs demonstrated altered homing capacities. Xenotransplantation of circulating HSPCs in humanised mice showed that human peripheral blood HSPCs possess the ability for extramedullary organ colonisation to the kidneys. Circulating and bone marrow-derived HSPCs are distinct in steady and diseased states. Patrolling SLE CD34+ HSPCs are able to home at extramedullary sites such as the spleen and kidneys, potentially participating in peripheral tissue injury.
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43
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Thiruvengadam M, Subramanian U, Venkidasamy B, Thirupathi P, Samynathan R, Shariati MA, Rebezov M, Chung IM, Rengasamy KRR. Emerging role of nutritional short-chain fatty acids (SCFAs) against cancer via modulation of hematopoiesis. Crit Rev Food Sci Nutr 2021; 63:827-844. [PMID: 34319824 DOI: 10.1080/10408398.2021.1954874] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The understanding of gut microbiota has emerged as a significant frontier in development of strategies to maintain normal human body's homeostasis and preventing the disease development over the last decade. The composition of the gut microbiota influences the clinical benefit of immune checkpoints in patients with advanced cancer, but the mechanisms underlying this relationship are unclear. Cancer is among the leading causes of mortality worldwide. So far, there is no universal treatment for cancer and despite significant advances, a lot of improvement on cancer therapy is required. Owing to its role in preserving the host's health and maintaining cellular integrity, the human gut microbiome has recently drawn a lot of interest as a target for cancer treatment. Dietary fiber is fermented by the gut microbiota to generate short-chain fatty acids (SCFAs), such as acetate, butyrate, and propionate, which are physiologically active metabolites. SCFAs can modulate the pathophysiology of the tumor environment through various critical signaling pathways. In addition, SCFAs can bind to carcinogens and other toxic chemicals, thus facilitating their biotransformation and elimination through different excretory mechanisms. This review discusses the mechanisms of action of short-chain fatty acids in modulating hematopoiesis of various immune system cells and the resultant beneficial anti-cancer effects. It also provides future perspectives on cancer therapy.
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Affiliation(s)
- Muthu Thiruvengadam
- Department of Crop Science, College of Sanghuh Life Science, Konkuk University, Seoul, Republic of Korea
| | - Umadevi Subramanian
- Translational Research Platform for Veterinary Biologicals, Tamil Nadu Veterinary and Animal Sciences University, Chennai, India
| | - Baskar Venkidasamy
- Department of Biotechnology, Sri Shakthi Institute of Engineering and Technology, Coimbatore, India
| | - Prabhu Thirupathi
- Translational Research Platform for Veterinary Biologicals, Tamil Nadu Veterinary and Animal Sciences University, Chennai, India
| | | | - Mohammad Ali Shariati
- Department of Technology of Food Products, K.G. Razumovsky Moscow State University of Technologies and Management (The First Cossack University), Moscow, Russian Federation
| | - Maksim Rebezov
- V M Gorbatov Federal Research Center for Food Systems of Russian Academy of Sciences, Moscow, Russian Federation.,Prokhorov General Physics Institute of the Russian Academy of Science, Moscow, Russian Federation
| | - Ill-Min Chung
- Department of Crop Science, College of Sanghuh Life Science, Konkuk University, Seoul, Republic of Korea
| | - Kannan R R Rengasamy
- Green Biotechnologies Research Centre of Excellence, University of Limpopo, Mankweng, South Africa
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44
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Kassiteridi C, Cole JE, Griseri T, Falck-Hansen M, Goddard ME, Seneviratne AN, Green PA, Park I, Shami AG, Pattarabanjird T, Upadhye A, Taylor AM, Handa A, Channon KM, Lutgens E, McNamara CA, Williams RO, Monaco C. CD200 Limits Monopoiesis and Monocyte Recruitment in Atherosclerosis. Circ Res 2021; 129:280-295. [PMID: 33975450 PMCID: PMC8260471 DOI: 10.1161/circresaha.119.316062] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 05/06/2021] [Accepted: 05/10/2021] [Indexed: 12/26/2022]
Abstract
[Figure: see text].
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Animals
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Aorta/immunology
- Aorta/metabolism
- Aorta/pathology
- Aortic Diseases/genetics
- Aortic Diseases/immunology
- Aortic Diseases/metabolism
- Aortic Diseases/pathology
- Atherosclerosis/genetics
- Atherosclerosis/immunology
- Atherosclerosis/metabolism
- Atherosclerosis/pathology
- Cells, Cultured
- Chemotaxis, Leukocyte
- Coronary Artery Disease/diagnostic imaging
- Coronary Artery Disease/immunology
- Coronary Artery Disease/metabolism
- Disease Models, Animal
- Female
- Humans
- Leukopoiesis
- Macrophages/immunology
- Macrophages/metabolism
- Male
- Membrane Glycoproteins/metabolism
- Mice, Inbred C57BL
- Mice, Knockout, ApoE
- Middle Aged
- Monocytes/immunology
- Monocytes/metabolism
- Orexin Receptors/metabolism
- Phosphorylation
- Plaque, Atherosclerotic
- STAT1 Transcription Factor/metabolism
- Signal Transduction
- Mice
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Affiliation(s)
- Christina Kassiteridi
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
| | - Jennifer E. Cole
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
| | - Thibault Griseri
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
| | - Mika Falck-Hansen
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
| | - Michael E. Goddard
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
| | - Anusha N. Seneviratne
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
| | - Patricia A. Green
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
| | - Inhye Park
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
| | - Annelie G. Shami
- Experimental Vascular Biology Division, Department of Medical Biochemistry, Amsterdam UMC, the Netherlands (A.G.S.,)
| | | | - Aditi Upadhye
- Cardiovascular Research Center, University of Virginia (T.P., A.U., A.M.T., C.A.M.)
| | - Angela M. Taylor
- Cardiovascular Research Center, University of Virginia (T.P., A.U., A.M.T., C.A.M.)
| | - Ashok Handa
- Nuffield Department of Surgical Sciences (A.H.), University of Oxford, UK
| | - Keith M. Channon
- Radcliffe Department of Medicine, RDM Cardiovascular Medicine (K.M.C.), University of Oxford, UK
| | - Esther Lutgens
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, München, Germany & German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany (E.L.)
| | - Coleen A. McNamara
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
- Cardiovascular Research Center, University of Virginia (T.P., A.U., A.M.T., C.A.M.)
| | - Richard O. Williams
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
| | - Claudia Monaco
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
- Nuffield Department of Surgical Sciences (A.H.), University of Oxford, UK
- Radcliffe Department of Medicine, RDM Cardiovascular Medicine (K.M.C.), University of Oxford, UK
- Experimental Vascular Biology Division, Department of Medical Biochemistry, Amsterdam UMC, the Netherlands (A.G.S.,)
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, München, Germany & German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany (E.L.)
- Cardiovascular Research Center, University of Virginia (T.P., A.U., A.M.T., C.A.M.)
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45
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Grzywa TM, Nowis D, Golab J. The role of CD71 + erythroid cells in the regulation of the immune response. Pharmacol Ther 2021; 228:107927. [PMID: 34171326 DOI: 10.1016/j.pharmthera.2021.107927] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/13/2021] [Accepted: 05/18/2021] [Indexed: 02/07/2023]
Abstract
Complex regulation of the immune response is necessary to support effective defense of an organism against hostile invaders and to maintain tolerance to harmless microorganisms and autoantigens. Recent studies revealed previously unappreciated roles of CD71+ erythroid cells (CECs) in regulation of the immune response. CECs physiologically reside in the bone marrow where erythropoiesis takes place. Under stress conditions, CECs are enriched in some organs outside of the bone marrow as a result of extramedullary erythropoiesis. However, the role of CECs goes well beyond the production of erythrocytes. In neonates, increased numbers of CECs contribute to their vulnerability to infectious diseases. On the other side, neonatal CECs suppress activation of immune cells in response to abrupt colonization with commensal microorganisms after delivery. CECs are also enriched in the peripheral blood of pregnant women as well as in the placenta and are responsible for the regulation of feto-maternal tolerance. In patients with cancer, anemia leads to increased frequency of CECs in the peripheral blood contributing to diminished antiviral and antibacterial immunity, as well as to accelerated cancer progression. Moreover, recent studies revealed the role of CECs in HIV and SARS-CoV-2 infections. CECs use a full arsenal of mechanisms to regulate immune response. These cells suppress proinflammatory responses of myeloid cells and T-cell proliferation by the depletion of ʟ-arginine by arginase. Moreover, CECs produce reactive oxygen species to decrease T-cell proliferation. CECs also secrete cytokines, including transforming growth factor β (TGF-β), which promotes T-cell differentiation into regulatory T-cells. Here, we comprehensively describe the role of CECs in orchestrating immune response and indicate some therapeutic approaches that might be used to regulate their effector functions in the treatment of human conditions.
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Affiliation(s)
- Tomasz M Grzywa
- Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Doctoral School, Medical University of Warsaw, Zwirki and Wigury 61 Street, 02-091 Warsaw, Poland; Laboratory of Experimental Medicine, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland.
| | - Dominika Nowis
- Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Laboratory of Experimental Medicine, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland.
| | - Jakub Golab
- Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Centre of Preclinical Research, Medical University of Warsaw, Banacha 1b Street, 02-097 Warsaw, Poland.
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46
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Caiado F, Pietras EM, Manz MG. Inflammation as a regulator of hematopoietic stem cell function in disease, aging, and clonal selection. J Exp Med 2021; 218:212381. [PMID: 34129016 PMCID: PMC8210622 DOI: 10.1084/jem.20201541] [Citation(s) in RCA: 161] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/19/2021] [Accepted: 05/19/2021] [Indexed: 12/17/2022] Open
Abstract
Inflammation is an evolutionarily selected defense response to infection or tissue damage that involves activation and consumption of immune cells in order to reestablish and maintain organismal integrity. In this process, hematopoietic stem cells (HSCs) are themselves exposed to inflammatory cues and via proliferation and differentiation, replace mature immune cells in a demand-adapted fashion. Here, we review how major sources of systemic inflammation act on and subsequently shape HSC fate and function. We highlight how lifelong inflammatory exposure contributes to HSC inflamm-aging and selection of premalignant HSC clones. Finally, we explore emerging areas of interest and open questions remaining in the field.
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Affiliation(s)
- Francisco Caiado
- Department of Medical Oncology and Hematology, University Hospital Zürich, Zürich, Switzerland.,University of Zürich, Comprehensive Cancer Center Zürich, Zürich, Switzerland
| | - Eric M Pietras
- Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Markus G Manz
- Department of Medical Oncology and Hematology, University Hospital Zürich, Zürich, Switzerland.,University of Zürich, Comprehensive Cancer Center Zürich, Zürich, Switzerland
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47
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Collins A, Mitchell CA, Passegué E. Inflammatory signaling regulates hematopoietic stem and progenitor cell development and homeostasis. J Exp Med 2021; 218:212383. [PMID: 34129018 PMCID: PMC8210624 DOI: 10.1084/jem.20201545] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 04/19/2021] [Accepted: 05/07/2021] [Indexed: 01/06/2023] Open
Abstract
Inflammation exerts multiple effects on the early hematopoietic compartment. Best studied is the role of proinflammatory cytokines in activating adult hematopoietic stem and progenitor cells to dynamically replenish myeloid lineage cells in a process known as emergency myelopoiesis. However, it is increasingly appreciated that the same proinflammatory signaling pathways are used in diverse hematopoietic scenarios. This review focuses on inflammatory signaling in the emergence of the definitive hematopoietic compartment during embryonic life, and tonic inflammatory signals derived from commensal microbiota in shaping the adult hematopoietic compartment in the absence of pathogenic insults. Insights into the unique and shared aspects of inflammatory signaling that regulate hematopoietic stem and progenitor cell function across the lifespan and health span of an individual will enable better diagnostic and therapeutic approaches to hematopoietic dysregulation and malignancies.
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Affiliation(s)
- Amélie Collins
- Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY.,Department of Pediatrics, Columbia University Irving Medical Center, New York, NY
| | - Carl A Mitchell
- Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY.,Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY
| | - Emmanuelle Passegué
- Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY.,Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY
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48
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Jung H, Kim JS, Lee KH, Tizaoui K, Terrazzino S, Cargnin S, Smith L, Koyanagi A, Jacob L, Li H, Hong SH, Yon DK, Lee SW, Kim MS, Wasuwanich P, Karnsakul W, Shin JI, Kronbichler A. Roles of microRNAs in inflammatory bowel disease. Int J Biol Sci 2021; 17:2112-2123. [PMID: 34131410 PMCID: PMC8193269 DOI: 10.7150/ijbs.59904] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 05/08/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract that mainly affects young people. IBD is associated with various gastrointestinal symptoms, and thus, affects the quality of life of patients. Currently, the pathogenesis of IBD is poorly understood. Although intestinal bacteria and host immune response are thought to be major factors in its pathogenesis, a sufficient explanation of their role in its pathophysiologic mechanism has not been presented. MicroRNAs (miRNAs), which are small RNA molecules that regulate gene expression, have gained attention as they are known to participate in the molecular interactions of IBD. Recent studies have confirmed the important role of miRNAs in targeting certain molecules in signaling pathways that regulate the homeostasis of the intestinal barrier, inflammatory reactions, and autophagy of the intestinal epithelium. Several studies have identified the specific miRNAs associated with IBD from colon tissues or serum samples of IBD patients and have attempted to use them as useful diagnostic biomarkers. Furthermore, some studies have attempted to treat IBD through intracolonic administration of specific miRNAs in the form of nanoparticle. This review summarizes the latest findings on the role of miRNAs in the pathogenesis, diagnosis, and treatment of IBD.
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Affiliation(s)
- HyunTaek Jung
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae Seok Kim
- Department of Nephrology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Keum Hwa Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kalthoum Tizaoui
- Laboratory Microorganisms and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Salvatore Terrazzino
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy
| | - Sarah Cargnin
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy
| | - Lee Smith
- The Cambridge Centre for Sport and Exercise Science, Anglia Ruskin University, Cambridge, CB1 1PT, UK
| | - Ai Koyanagi
- Research and Development Unit, Parc Sanitari Sant Joan de Déu, CIBERSAM, 08830 Barcelona, Spain.,ICREA, Pg. Lluis Companys 23, 08010 Barcelona, Spain
| | - Louis Jacob
- Research and Development Unit, Parc Sanitari Sant Joan de Déu, CIBERSAM, 08830 Barcelona, Spain.,Faculty of Medicine, University of Versailles Saint-Quentin-en-Yvelines, 78000 Versailles, France
| | - Han Li
- University of Florida College of Medicine, Gainesville, FL 32610, USA
| | - Sung Hwi Hong
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dong Keon Yon
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seung Won Lee
- Department of Data Science, Sejong University College of Software Convergence, Seoul, Republic of Korea
| | - Min Seo Kim
- Korea University, College of Medicine, Seoul, Republic of Korea
| | - Paul Wasuwanich
- University of Florida College of Medicine, Gainesville, FL 32610, USA
| | - Wikrom Karnsakul
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Andreas Kronbichler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
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49
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Rohm TV, Fuchs R, Müller RL, Keller L, Baumann Z, Bosch AJT, Schneider R, Labes D, Langer I, Pilz JB, Niess JH, Delko T, Hruz P, Cavelti-Weder C. Obesity in Humans Is Characterized by Gut Inflammation as Shown by Pro-Inflammatory Intestinal Macrophage Accumulation. Front Immunol 2021; 12:668654. [PMID: 34054838 PMCID: PMC8158297 DOI: 10.3389/fimmu.2021.668654] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 04/26/2021] [Indexed: 12/17/2022] Open
Abstract
Chronic low-grade inflammation is a hallmark of obesity and associated with cardiovascular complications. However, it remains unclear where this inflammation starts. As the gut is constantly exposed to food, gut microbiota, and metabolites, we hypothesized that mucosal immunity triggers an innate inflammatory response in obesity. We characterized five distinct macrophage subpopulations (P1-P5) along the gastrointestinal tract and blood monocyte subpopulations (classical, non-classical, intermediate), which replenish intestinal macrophages, in non-obese (BMI<27kg/m2) and obese individuals (BMI>32kg/m2). To elucidate factors that potentially trigger gut inflammation, we correlated these subpopulations with cardiovascular risk factors and lifestyle behaviors. In obese individuals, we found higher pro-inflammatory macrophages in the stomach, duodenum, and colon. Intermediate blood monocytes were also increased in obesity, suggesting enhanced recruitment to the gut. We identified unhealthy lifestyle habits as potential triggers of gut and systemic inflammation (i.e., low vegetable intake, high processed meat consumption, sedentary lifestyle). Cardiovascular risk factors other than body weight did not affect the innate immune response. Thus, obesity in humans is characterized by gut inflammation as shown by accumulation of pro-inflammatory intestinal macrophages, potentially via recruited blood monocytes. Understanding gut innate immunity in human obesity might open up new targets for immune-modulatory treatments in metabolic disease.
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Affiliation(s)
- Theresa V Rohm
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Regula Fuchs
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland
| | - Rahel L Müller
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland
| | - Lena Keller
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Zora Baumann
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland.,Department of Surgery, University Hospital Basel, Basel, Switzerland
| | - Angela J T Bosch
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Romano Schneider
- Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland.,Clarunis, Department of Visceral Surgery, University Center for Gastrointestinal and Liver Diseases Basel, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Danny Labes
- Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland
| | - Igor Langer
- Department of Visceral Surgery, Lindenhof Hospital, Bern, Switzerland
| | - Julia B Pilz
- AMB-Arztpraxis MagenDarm Basel, Basel and MagenDarm Aarau, Aarau, Switzerland
| | - Jan H Niess
- Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland.,Clarunis, Department of Visceral Surgery, University Center for Gastrointestinal and Liver Diseases Basel, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Tarik Delko
- Clarunis, Department of Visceral Surgery, University Center for Gastrointestinal and Liver Diseases Basel, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Petr Hruz
- Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland.,Clarunis, Department of Visceral Surgery, University Center for Gastrointestinal and Liver Diseases Basel, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Claudia Cavelti-Weder
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, Basel, Switzerland.,Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
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50
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Hegde S, Leader AM, Merad M. MDSC: Markers, development, states, and unaddressed complexity. Immunity 2021; 54:875-884. [PMID: 33979585 DOI: 10.1016/j.immuni.2021.04.004] [Citation(s) in RCA: 409] [Impact Index Per Article: 102.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 01/20/2021] [Accepted: 04/08/2021] [Indexed: 12/19/2022]
Abstract
Myeloid-derived suppressor cells (MDSCs) are one of the most discussed biological entities in immunology. While the context and classification of this group of cells has evolved, MDSCs most commonly describe cells arising during chronic inflammation, especially late-stage cancers, and are defined by their T cell immunosuppressive functions. This MDSC concept has helped explain myeloid phenomena associated with disease outcome, but currently lacks clear definitions and a unifying framework across pathologies. Here, we propose such a framework to classify MDSCs as discrete cell states based on activation signals in myeloid populations leading to suppressive modes characterized by specific, measurable effects. Developing this level of knowledge of myeloid states across pathological conditions may ultimately transform how disparate diseases are grouped and treated.
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Affiliation(s)
- Samarth Hegde
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Andrew M Leader
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Miriam Merad
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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