|
1
|
García-Domínguez M. The Role of IL-23 in the Development of Inflammatory Diseases. BIOLOGY 2025; 14:347. [PMID: 40282212 PMCID: PMC12025033 DOI: 10.3390/biology14040347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Revised: 03/23/2025] [Accepted: 03/25/2025] [Indexed: 04/29/2025]
Abstract
Interleukin-23 is crucial in the initiation and progression of certain inflammatory disorders. As a key cytokine, IL-23 is involved in the differentiation and activation of Th17 cells, which play a role in a broad spectrum of inflammatory diseases. This review examines the molecular mechanisms through which IL-23 contributes to the pathogenesis of conditions including psoriasis, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. By elucidating the significant role of IL-23 in inflammation, this review underscores its importance as a therapeutic target for managing inflammatory conditions, with particular emphasis on current and emerging biologic treatments.
Collapse
Affiliation(s)
- Mario García-Domínguez
- Program of Immunology and Immunotherapy, CIMA-Universidad de Navarra, 31008 Pamplona, Spain;
- Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| |
Collapse
|
|
2
|
Wang X, Hong Y, Zou J, Zhu B, Jiang C, Lu L, Tian J, Yang J, Rui K. The role of BATF in immune cell differentiation and autoimmune diseases. Biomark Res 2025; 13:22. [PMID: 39876010 PMCID: PMC11776340 DOI: 10.1186/s40364-025-00733-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 01/17/2025] [Indexed: 01/30/2025] Open
Abstract
As a member of the Activator Protein-1 (AP-1) transcription factor family, the Basic Leucine Zipper Transcription Factor (BATF) mediates multiple biological functions of immune cells through its involvement in protein interactions and binding to DNA. Recent studies have demonstrated that BATF not only plays pivotal roles in innate and adaptive immune responses but also acts as a crucial factor in the differentiation and function of various immune cells. Lines of evidence indicate that BATF is associated with the onset and progression of allergic diseases, graft-versus-host disease, tumors, and autoimmune diseases. This review summarizes the roles of BATF in the development and function of innate and adaptive immune cells, as well as its immunoregulatory effects in the development of autoimmune diseases, which may enhance the current understanding of the pathogenesis of autoimmune diseases and facilitate the development of new therapeutic strategies.
Collapse
Affiliation(s)
- Xiaomeng Wang
- Department of Laboratory Medicine, Institute of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yue Hong
- Department of Hematology and Oncology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Jinmei Zou
- Department of Rheumatology, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, China
| | - Bo Zhu
- Department of Laboratory Medicine, Institute of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Chao Jiang
- Department of Orthopaedics, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Liwei Lu
- Department of Pathology, Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China
| | - Jie Tian
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China.
| | - Jing Yang
- Department of Rheumatology, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, China.
| | - Ke Rui
- Department of Laboratory Medicine, Institute of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
| |
Collapse
|
|
3
|
Audia S, Brescia C, Dattilo V, Torchia N, Trapasso F, Amato R. The IL-23R and Its Genetic Variants: A Hitherto Unforeseen Bridge Between the Immune System and Cancer Development. Cancers (Basel) 2024; 17:55. [PMID: 39796684 PMCID: PMC11718844 DOI: 10.3390/cancers17010055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 12/20/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
IL-23R (interleukin-23 receptor), found on the surface of several immune cells, plays a key role in the immune system. Indeed, this process is not limited to the inflammatory response but also plays a role in the adaptive immune response. The binding between IL-23R and its specific ligand, the interleukin 23, initiates a number of specific signals by modulating both properties and behavior of immune cells. In particular, it is critical for the regulation of T helper 17 cells (Th17). Th17s are a subset of T cells involved in autoimmune and inflammatory diseases, as well as in cancer. The clinical relevance of IL-23R is underscored by its association with an elevated susceptibility or diminished vulnerability to a spectrum of diseases, including psoriasis, ankylosing spondylitis, and inflammatory bowel disease (IBD). Evidence has emerged that suggests it may also serve to predict both tumor progression and therapeutic responsiveness. It is noteworthy that the IL-23/IL-23R pathway is emerging as a promising therapeutic target. A number of biologic drugs, such as monoclonal antibodies, are currently developing with the aim of blocking this interaction, thus reducing inflammation. This represents a significant advancement in the field of medicine, offering new hope for pursuing more effective and personalized treatments. Recent studies have also investigated the role of such a pathway in autoimmune diseases, and its potential impact on infections as well as in carcinogenesis. The aim of this review is to focus on the role of IL-23R in immune genetics and its potential for modulating the natural history of neoplastic disease.
Collapse
Affiliation(s)
- Salvatore Audia
- Immuno-Genetics Lab, Department of Health Science, Medical School, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (C.B.); (N.T.)
| | - Carolina Brescia
- Immuno-Genetics Lab, Department of Health Science, Medical School, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (C.B.); (N.T.)
| | - Vincenzo Dattilo
- Department of Experimental and Clinical Medicine, Medical School, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy;
| | - Naomi Torchia
- Immuno-Genetics Lab, Department of Health Science, Medical School, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (C.B.); (N.T.)
| | - Francesco Trapasso
- Department of Experimental and Clinical Medicine, Medical School, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy;
| | - Rosario Amato
- Immuno-Genetics Lab, Department of Health Science, Medical School, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (C.B.); (N.T.)
| |
Collapse
|
|
4
|
Moond V, Maniyar B, Harne PS, Bailey-Lundberg JM, Thosani NC. Harnessing endoscopic ultrasound-guided radiofrequency ablation to reshape the pancreatic ductal adenocarcinoma microenvironment and elicit systemic immunomodulation. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:1056-1073. [PMID: 39351436 PMCID: PMC11438557 DOI: 10.37349/etat.2024.00263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 06/19/2024] [Indexed: 10/04/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognostics and substantial therapeutic challenges, with dismal survival rates. Tumor resistance in PDAC is primarily attributed to its fibrotic, hypoxic, and immune-suppressive tumor microenvironment (TME). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA), an Food and Drug Administration (FDA)-approved minimally invasive technique for treating pancreatic cancer, disrupts tumors with heat and induces coagulative necrosis, releasing tumor antigens that may trigger a systemic immune response-the abscopal effect. We aim to elucidate the roles of EUS-RFA-mediated thermal and mechanical stress in enhancing anti-tumor immunity in PDAC. A comprehensive literature review focused on radiofrequency immunomodulation and immunotherapy in pancreatic tumors to understand the pathophysiological mechanisms of RFA and its effect on the TME, which could prevent recurrence and resistance. We reviewed clinical, preclinical, and in vitro studies on RFA mechanisms in pancreatic adenocarcinoma, discussing the unique immunomodulatory effects of EUS-RFA. Recent findings suggest that combining RFA with immune adjuvants enhances responses in pancreatic adenocarcinoma. EUS-RFA offers a dual benefit against PDAC by directly reducing tumor viability and indirectly enhancing anti-tumor immunity. Observations of neutrophil-mediated immunomodulation and programmed cell death ligand 1 (PD-L1) modulation support integrating EUS-RFA with targeted immunotherapies for managing pancreatic adenocarcinoma. Integrating EUS-RFA in PDAC treatment promises direct cytoreduction and synergistic effects with molecular targeted therapies. Prospective clinical trials are crucial to assess the efficacy of this combined approach in improving outcomes and survival rates in advanced PDAC cases.
Collapse
Affiliation(s)
- Vishali Moond
- Department of Internal Medicine, Saint Peter’s University Hospital/Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
| | - Bhumi Maniyar
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030, USA
- Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, University of Texas Health Science Center, Houston, TX 77030, USA
| | - Prateek Suresh Harne
- Department of Gastroenterology and Hepatology, University of Texas Health Science Center, Houston McGovern Medical School, Houston TX 77030, USA
| | - Jennifer M. Bailey-Lundberg
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030, USA
- Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, University of Texas Health Science Center, Houston, TX 77030, USA
| | - Nirav C. Thosani
- Department of Internal Medicine, Saint Peter’s University Hospital/Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
- Division of Elective Surgery and Interventional Gastroenterology, Department of Surgery, University of Texas Health Science Center, Houston TX 77030, USA
| |
Collapse
|
|
5
|
Lee KMC, Lupancu T, Chang L, Manthey CL, Zeeman M, Fourie AM, Hamilton JA. The mode of action of IL-23 in experimental inflammatory arthritic pain and disease. Arthritis Res Ther 2024; 26:148. [PMID: 39107827 PMCID: PMC11302168 DOI: 10.1186/s13075-024-03380-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 07/22/2024] [Indexed: 08/10/2024] Open
Abstract
OBJECTIVES We have previously reported using gene-deficient mice that the interleukin (IL)-23p19 subunit is required for the development of innate immune-driven arthritic pain and disease. We aimed to explore here, using a number of in vivo approaches, how the IL-23p19 subunit can mechanistically control arthritic pain and disease in a T- and B- lymphocyte-independent manner. METHODS We used the zymosan-induced arthritis (ZIA) model in wild-type and Il23p19-/- mice, by a radiation chimera approach, and by single cell RNAseq and qPCR analyses, to identify the IL23p19-expressing and IL-23-responding cell type(s) in the inflamed joints. This model was also utilized to investigate the efficacy of IL-23p19 subunit blockade with a neutralizing monoclonal antibody (mAb). A novel IL-23-driven arthritis model was established, allowing the identification of putative downstream mediators of IL-23 in the control of pain and disease. Pain and arthritis were assessed by relative static weight distribution and histology, respectively. RESULTS We present evidence that (i) IL-23p19+ non-bone marrow-derived macrophages are required for the development of ZIA pain and disease, (ii) prophylactic and therapeutic blockade of the IL-23p19 subunit ameliorate ZIA pain and disease and (iii) systemically administered IL-23 can induce arthritic pain and disease in a manner dependent on TNF, GM-CSF, CCL17 and cyclooxygenase activity, but independently of lymphocytes, CGRP, NGF and substance P. CONCLUSIONS The data presented should aid IL-23 targeting both in the choice of inflammatory disease to be treated and the design of clinical trials.
Collapse
Affiliation(s)
- Kevin M-C Lee
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia.
| | - Tanya Lupancu
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia
| | - Leon Chang
- Janssen Research & Development, San Diego, CA, USA
| | | | - Martha Zeeman
- Janssen Research & Development, Spring House, PA, USA
| | | | - John A Hamilton
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia
| |
Collapse
|
|
6
|
Pilkington AW, Buragamadagu B, Johnston RA. Weighted Breaths: Exploring Biologic and Non-Biologic Therapies for Co-Existing Asthma and Obesity. Curr Allergy Asthma Rep 2024; 24:381-393. [PMID: 38878250 PMCID: PMC11233394 DOI: 10.1007/s11882-024-01153-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] [Accepted: 05/21/2024] [Indexed: 07/10/2024]
Abstract
PURPOSE OF REVIEW To discuss the effectiveness of biologics, some of which comprise the newest class of asthma controller medications, and non-biologics in the treatment of asthma co-existing with obesity. RECENT FINDINGS Our review of recent preliminary and published data from clinical trials revealed that obese asthmatics respond favorably to dupilumab, mepolizumab, omalizumab, and tezepelumab, which are biologics currently indicated as add-on maintenance therapy for severe asthma. Furthermore, clinical trials are ongoing to assess the efficacy of non-biologics in the treatment of obese asthma, including a glucagon-like peptide-1 receptor agonist, a Janus kinase inhibitor, and probiotics. Although many biologics presently indicated as add-on maintenance therapy for severe asthma exhibit efficacy in obese asthmatics, other phenotypes of asthma co-existing with obesity may be refractory to these medications. Thus, to improve quality of life and asthma control, it is imperative to identify therapeutic options for all existing phenotypes of obese asthma.
Collapse
Affiliation(s)
- Albert W Pilkington
- Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, United States Department of Health and Human Services, 1000 Frederick Lane, Morgantown, WV, 26508-5402, USA
| | - Bhanusowmya Buragamadagu
- Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, School of Medicine, West Virginia University, Morgantown, WV, USA
| | - Richard A Johnston
- Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, United States Department of Health and Human Services, 1000 Frederick Lane, Morgantown, WV, 26508-5402, USA.
- Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, School of Medicine, West Virginia University, Morgantown, WV, USA.
- Department of Physiology, Pharmacology, and Toxicology, School of Medicine, West Virginia University, Morgantown, WV, USA.
| |
Collapse
|
|
7
|
Carnevale S, Ponzetta A, Rigatelli A, Carriero R, Puccio S, Supino D, Grieco G, Molisso P, Di Ceglie I, Scavello F, Perucchini C, Pasqualini F, Recordati C, Tripodo C, Belmonte B, Mariancini A, Kunderfranco P, Sciumè G, Lugli E, Bonavita E, Magrini E, Garlanda C, Mantovani A, Jaillon S. Neutrophils Mediate Protection Against Colitis and Carcinogenesis by Controlling Bacterial Invasion and IL22 Production by γδ T Cells. Cancer Immunol Res 2024; 12:413-426. [PMID: 38349973 PMCID: PMC10985471 DOI: 10.1158/2326-6066.cir-23-0295] [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: 04/07/2023] [Revised: 12/01/2023] [Accepted: 02/09/2024] [Indexed: 02/15/2024]
Abstract
Neutrophils are the most abundant leukocytes in human blood and play a primary role in resistance against invading microorganisms and in the acute inflammatory response. However, their role in colitis and colitis-associated colorectal cancer is still under debate. This study aims to dissect the role of neutrophils in these pathologic contexts by using a rigorous genetic approach. Neutrophil-deficient mice (Csf3r-/- mice) were used in classic models of colitis and colitis-associated colorectal cancer and the role of neutrophils was assessed by histologic, cellular, and molecular analyses coupled with adoptive cell transfer. We also performed correlative analyses using human datasets. Csf3r-/- mice showed increased susceptibility to colitis and colitis-associated colorectal cancer compared with control Csf3r+/+ mice and adoptive transfer of neutrophils in Csf3r-/- mice reverted the phenotype. In colitis, Csf3r-/- mice showed increased bacterial invasion and a reduced number of healing ulcers in the colon, indicating a compromised regenerative capacity of epithelial cells. Neutrophils were essential for γδ T-cell polarization and IL22 production. In patients with ulcerative colitis, expression of CSF3R was positively correlated with IL22 and IL23 expression. Moreover, gene signatures associated with epithelial-cell development, proliferation, and antimicrobial response were enriched in CSF3Rhigh patients. Our data support a model where neutrophils mediate protection against intestinal inflammation and colitis-associated colorectal cancer by controlling the intestinal microbiota and driving the activation of an IL22-dependent tissue repair pathway.
Collapse
Affiliation(s)
| | | | - Anna Rigatelli
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | | | - Simone Puccio
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Institute of Genetic and Biomedical Research, UoS Milan, National Research Council, Milan, Italy
| | | | - Giovanna Grieco
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Piera Molisso
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele, Milan, Italy
| | | | | | | | - Fabio Pasqualini
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Camilla Recordati
- Department of Veterinary Medicine and Animal Sciences, University of Milan, Mouse & Animal Pathology Laboratory (MAPLab), UniMi Foundation, Milan, Italy
| | - Claudio Tripodo
- Tumor Immunology Unit, Department of Health Science, University of Palermo, School of Medicine, Palermo, Italy
| | - Beatrice Belmonte
- Tumor Immunology Unit, Department of Health Science, University of Palermo, School of Medicine, Palermo, Italy
| | - Andrea Mariancini
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele, Milan, Italy
| | | | - Giuseppe Sciumè
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy
| | - Enrico Lugli
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Eduardo Bonavita
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Elena Magrini
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Cecilia Garlanda
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Alberto Mantovani
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele, Milan, Italy
- The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Sebastien Jaillon
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele, Milan, Italy
| |
Collapse
|
|
8
|
Mezghiche I, Yahia-Cherbal H, Rogge L, Bianchi E. Interleukin 23 receptor: Expression and regulation in immune cells. Eur J Immunol 2024; 54:e2250348. [PMID: 37837262 DOI: 10.1002/eji.202250348] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/11/2023] [Accepted: 10/12/2023] [Indexed: 10/15/2023]
Abstract
The importance of IL-23 and its specific receptor, IL-23R, in the pathogenesis of several chronic inflammatory diseases has been established, but the underlying pathological mechanisms are not fully understood. This review focuses on IL-23R expression and regulation in immune cells.
Collapse
Affiliation(s)
| | | | - Lars Rogge
- Institut Pasteur, Université Paris Cité, Paris, France
| | | |
Collapse
|
|
9
|
Wu C, Xu J, Zhang Z, Wei D, Xu Y, Zhao Y. The Effects of IL-23/IL-18-Polarized Neutrophils on Renal Ischemia-Reperfusion Injury and Allogeneic-Skin-Graft Rejection in Mice. Biomedicines 2023; 11:3148. [PMID: 38137369 PMCID: PMC10740676 DOI: 10.3390/biomedicines11123148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 10/26/2023] [Accepted: 11/20/2023] [Indexed: 12/24/2023] Open
Abstract
Neutrophils display heterogeneity and plasticity with different subgroups and immune-regulatory functions under various surrounding conditions. Neutrophils induced by IL-23/IL-18 (referred to N(IL-23+IL-18) neutrophils) have a unique gene-expression profile, with highly expressing IL-17, MHC-II, and costimulatory molecules. The adoptive transfer of N(IL-23+IL-18) neutrophils significantly increased the pathogenesis in a renal ischemia-reperfusion injury mouse model. N(IL-23+IL-18) neutrophils directly and efficiently induced allogeneic T cell proliferation in vitro. N(IL-23+IL-18) neutrophils enhanced the syngeneic T cell response to allogeneic antigens in mixed-lymphocyte reaction assays. The adoptive transfer of the donor or host N(IL-23+IL-18) neutrophils significantly enhanced the antidonor antibody production in an allogeneic-skin-transplanted mouse model, accompanied by increased Tfh cells in the spleens. Therefore, the neutrophil subset induced by IL-23/IL-18 promotes tissue injury and antidonor humoral response in the allogeneic transplantation mouse model.
Collapse
Affiliation(s)
- Changhong Wu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100045, China; (C.W.); (J.X.); (Y.X.)
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Jinglin Xu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100045, China; (C.W.); (J.X.); (Y.X.)
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Zhaoqi Zhang
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (Z.Z.); (D.W.)
| | - Dong Wei
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (Z.Z.); (D.W.)
| | - Yanan Xu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100045, China; (C.W.); (J.X.); (Y.X.)
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100045, China; (C.W.); (J.X.); (Y.X.)
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (Z.Z.); (D.W.)
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Shenzhen 518055, China
| |
Collapse
|
|
10
|
Zec K, Thiebes S, Bottek J, Siemes D, Spangenberg P, Trieu DV, Kirstein N, Subramaniam N, Christ R, Klein D, Jendrossek V, Loose M, Wagenlehner F, Jablonska J, Bracht T, Sitek B, Budeus B, Klein-Hitpass L, Theegarten D, Shevchuk O, Engel DR. Comparative transcriptomic and proteomic signature of lung alveolar macrophages reveals the integrin CD11b as a regulatory hub during pneumococcal pneumonia infection. Front Immunol 2023; 14:1227191. [PMID: 37790937 PMCID: PMC10544576 DOI: 10.3389/fimmu.2023.1227191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 08/23/2023] [Indexed: 10/05/2023] Open
Abstract
Introduction Streptococcus pneumoniae is one of the main causes of community-acquired infections in the lung alveoli in children and the elderly. Alveolar macrophages (AM) patrol alveoli in homeostasis and under infectious conditions. However, the molecular adaptations of AM upon infections with Streptococcus pneumoniae are incompletely resolved. Methods We used a comparative transcriptomic and proteomic approach to provide novel insights into the cellular mechanism that changes the molecular signature of AM during lung infections. Using a tandem mass spectrometry approach to murine cell-sorted AM, we revealed significant proteomic changes upon lung infection with Streptococcus pneumoniae. Results AM showed a strong neutrophil-associated proteomic signature, such as expression of CD11b, MPO, neutrophil gelatinases, and elastases, which was associated with phagocytosis of recruited neutrophils. Transcriptomic analysis indicated intrinsic expression of CD11b by AM. Moreover, comparative transcriptomic and proteomic profiling identified CD11b as the central molecular hub in AM, which influenced neutrophil recruitment, activation, and migration. Discussion In conclusion, our study provides novel insights into the intrinsic molecular adaptations of AM upon lung infection with Streptococcus pneumoniae and reveals profound alterations critical for effective antimicrobial immunity.
Collapse
Affiliation(s)
- Kristina Zec
- Institute for Experimental Immunology and Imaging, Department of Immunodynamics, University Hospital Essen, Essen, Germany
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Stephanie Thiebes
- Institute for Experimental Immunology and Imaging, Department of Immunodynamics, University Hospital Essen, Essen, Germany
| | - Jenny Bottek
- Institute for Experimental Immunology and Imaging, Department of Immunodynamics, University Hospital Essen, Essen, Germany
| | - Devon Siemes
- Institute for Experimental Immunology and Imaging, Department of Immunodynamics, University Hospital Essen, Essen, Germany
| | - Philippa Spangenberg
- Institute for Experimental Immunology and Imaging, Department of Immunodynamics, University Hospital Essen, Essen, Germany
| | - Duc Viet Trieu
- Institute for Experimental Immunology and Imaging, Department of Immunodynamics, University Hospital Essen, Essen, Germany
| | - Nils Kirstein
- Institute for Experimental Immunology and Imaging, Department of Immunodynamics, University Hospital Essen, Essen, Germany
| | - Nirojah Subramaniam
- Institute for Experimental Immunology and Imaging, Department of Immunodynamics, University Hospital Essen, Essen, Germany
| | - Robin Christ
- Institute for Experimental Immunology and Imaging, Department of Immunodynamics, University Hospital Essen, Essen, Germany
| | - Diana Klein
- Institute for Cell Biology (Cancer Research), University Hospital Essen, Essen, Germany
| | - Verena Jendrossek
- Institute for Cell Biology (Cancer Research), University Hospital Essen, Essen, Germany
| | - Maria Loose
- Clinic for Urology, Paediatric Urology and Andrology, Justus-Liebig University of Giessen, Giessen, Germany
| | - Florian Wagenlehner
- Clinic for Urology, Paediatric Urology and Andrology, Justus-Liebig University of Giessen, Giessen, Germany
| | - Jadwiga Jablonska
- Department of Otorhinolaryngology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Thilo Bracht
- Medical Faculty, Medizinisches Proteom‐Center, Ruhr‐University Bochum, Bochum, Germany
- Clinic for Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Knappschafts-krankenhaus Bochum, Bochum, Germany
| | - Barbara Sitek
- Medical Faculty, Medizinisches Proteom‐Center, Ruhr‐University Bochum, Bochum, Germany
- Clinic for Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Knappschafts-krankenhaus Bochum, Bochum, Germany
| | - Bettina Budeus
- Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany
| | - Ludger Klein-Hitpass
- Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany
| | - Dirk Theegarten
- Institute of Pathology, University Hospital Essen, Essen, Germany
| | - Olga Shevchuk
- Institute for Experimental Immunology and Imaging, Department of Immunodynamics, University Hospital Essen, Essen, Germany
| | - Daniel R. Engel
- Institute for Experimental Immunology and Imaging, Department of Immunodynamics, University Hospital Essen, Essen, Germany
| |
Collapse
|
|
11
|
Jiang T, Tang XY, Mao Y, Zhou YQ, Wang JJ, Li RM, Xie XR, Zhang HM, Fang B, Ouyang NJ, Tang GH. Matrix mechanics regulate the polarization state of bone marrow-derived neutrophils through the JAK1/STAT3 signaling pathway. Acta Biomater 2023; 168:159-173. [PMID: 37467837 DOI: 10.1016/j.actbio.2023.07.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 07/11/2023] [Accepted: 07/11/2023] [Indexed: 07/21/2023]
Abstract
Matrix mechanics regulate essential cell behaviors through mechanotransduction, and as one of its most important elements, substrate stiffness was reported to regulate cell functions such as viability, communication, migration, and differentiation. Neutrophils (Neus) predominate the early inflammatory response and initiate regeneration. The activation of Neus can be regulated by physical cues; however, the functional alterations of Neus by substrate stiffness remain unknown, which is critical in determining the outcomes of engineered tissue mimics. Herein, a three-dimensional (3D) culture system made of hydrogels was developed to explore the effects of varying stiffnesses (1.5, 2.6, and 5.7 kPa) on the states of Neus. Neus showed better cell integrity and viability in the 3D system. Moreover, it was shown that the stiffer matrix tended to induce Neus toward an anti-inflammatory phenotype (N2) with less adhesion molecule expression, less reactive oxygen species (ROS) production, and more anti-inflammatory cytokine secretion. Additionally, the aortic ring assay indicated that Neus cultured in a stiffer matrix significantly increased vascular sprouting. RNA sequencing showed that a stiffer matrix could significantly activate JAK1/STAT3 signaling in Neus and the inhibition of JAK1 ablated the stiffness-dependent increase in the expression of CD182 (an N2 marker). Taken together, these results demonstrate that a stiffer matrix promotes Neus to shift to the N2 phenotype, which was regulated by JAK1/STAT3 pathway. This study lays the groundwork for further research on fabricating engineered tissue mimics, which may provide more treatment options for ischemic diseases and bone defects. STATEMENT OF SIGNIFICANCE.
Collapse
Affiliation(s)
- Ting Jiang
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, Shanghai 200011, PR China; Oral Bioengineering Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, PR China
| | - Xin-Yue Tang
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, Shanghai 200011, PR China; Oral Bioengineering Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, PR China
| | - Yi Mao
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, Shanghai 200011, PR China; Oral Bioengineering Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, PR China
| | - Yu-Qi Zhou
- Oral Bioengineering Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, PR China
| | - Jia-Jia Wang
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, Shanghai 200011, PR China; Oral Bioengineering Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, PR China
| | - Ruo-Mei Li
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, Shanghai 200011, PR China; Oral Bioengineering Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, PR China
| | - Xin-Ru Xie
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, Shanghai 200011, PR China; Oral Bioengineering Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, PR China
| | - Hong-Ming Zhang
- Oral Bioengineering Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, PR China
| | - Bing Fang
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, Shanghai 200011, PR China; Oral Bioengineering Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, PR China.
| | - Ning-Juan Ouyang
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, Shanghai 200011, PR China.
| | - Guo-Hua Tang
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, Shanghai 200011, PR China; Oral Bioengineering Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, PR China.
| |
Collapse
|
|
12
|
Chen Y, Zhao C, Guo H, Zou W, Zhang Z, Wei D, Lu H, Zhang L, Zhao Y. Wip1 inhibits neutrophil extracellular traps to promote abscess formation in mice by directly dephosphorylating Coronin-1a. Cell Mol Immunol 2023; 20:941-954. [PMID: 37386173 PMCID: PMC10387484 DOI: 10.1038/s41423-023-01057-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 06/04/2023] [Indexed: 07/01/2023] Open
Abstract
Neutrophil extracellular traps (NETs) participate in the rapid inhibition and clearance of pathogens during infection; however, the molecular regulation of NET formation remains poorly understood. In the current study, we found that inhibition of the wild-type p53-induced phosphatase 1 (Wip1) significantly suppressed the activity of Staphylococcus aureus (S. aureus) and accelerated abscess healing in S. aureus-induced abscess model mice by enhancing NET formation. A Wip1 inhibitor significantly enhanced NET formation in mouse and human neutrophils in vitro. High-resolution mass spectrometry and biochemical assays demonstrated that Coro1a is a substrate of Wip1. Further experiments also revealed that Wip1 preferentially and directly interacts with phosphorylated Coro1a than compared to unphosphorylated inactivated Coro1a. The phosphorylated Ser426 site of Coro1a and the 28-90 aa domain of Wip1 are essential for the direct interaction of Coro1a and Wip1 and for Wip1 dephosphorylation of p-Coro1a Ser426. Wip1 deletion or inhibition in neutrophils significantly upregulated the phosphorylation of Coro1a-Ser426, which activated phospholipase C and subsequently the calcium pathway, the latter of which promoted NET formation after infection or lipopolysaccharide stimulation. This study revealed Coro1a to be a novel substrate of Wip1 and showed that Wip1 is a negative regulator of NET formation during infection. These results support the potential application of Wip1 inhibitors to treat bacterial infections.
Collapse
Affiliation(s)
- Yifang Chen
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regeneration, Beijing, China
| | - Chenxu Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Han Guo
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Weilong Zou
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Zhaoqi Zhang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Dong Wei
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Hezhe Lu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
- Beijing Institute for Stem Cell and Regeneration, Beijing, China.
| | - Lianfeng Zhang
- Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health; Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Beijing, China.
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
- Beijing Institute for Stem Cell and Regeneration, Beijing, China.
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
| |
Collapse
|
|
13
|
Zhou W, Cao X, Xu Q, Qu J, Sun Y. The double-edged role of neutrophil heterogeneity in inflammatory diseases and cancers. MedComm (Beijing) 2023; 4:e325. [PMID: 37492784 PMCID: PMC10363828 DOI: 10.1002/mco2.325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 05/31/2023] [Accepted: 06/09/2023] [Indexed: 07/27/2023] Open
Abstract
Neutrophils are important immune cells act as the body's first line of defense against infection and respond to diverse inflammatory cues. Many studies have demonstrated that neutrophils display plasticity in inflammatory diseases and cancers. Clarifying the role of neutrophil heterogeneity in inflammatory diseases and cancers will contribute to the development of novel treatment strategies. In this review, we have presented a review on the development of the understanding on neutrophil heterogeneity from the traditional perspective and a high-resolution viewpoint. A growing body of evidence has confirmed the double-edged role of neutrophils in inflammatory diseases and tumors. This may be due to a lack of precise understanding of the role of specific neutrophil subsets in the disease. Thus, elucidating specific neutrophil subsets involved in diseases would benefit the development of precision medicine. Thusly, we have summarized the relevance and actions of neutrophil heterogeneity in inflammatory diseases and cancers comprehensively. Meanwhile, we also discussed the potential intervention strategy for neutrophils. This review is intended to deepen our understanding of neutrophil heterogeneity in inflammatory diseases and cancers, while hold promise for precise treatment of neutrophil-related diseases.
Collapse
Affiliation(s)
- Wencheng Zhou
- Department of PharmacyThe First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)HangzhouChina
| | - Xinran Cao
- State Key Laboratory of Pharmaceutical BiotechnologyDepartment of Biotechnology and Pharmaceutical SciencesSchool of Life ScienceNanjing UniversityNanjingChina
| | - Qiang Xu
- State Key Laboratory of Pharmaceutical BiotechnologyDepartment of Biotechnology and Pharmaceutical SciencesSchool of Life ScienceNanjing UniversityNanjingChina
| | - Jiao Qu
- State Key Laboratory of Pharmaceutical BiotechnologyDepartment of Biotechnology and Pharmaceutical SciencesSchool of Life ScienceNanjing UniversityNanjingChina
| | - Yang Sun
- State Key Laboratory of Pharmaceutical BiotechnologyDepartment of Biotechnology and Pharmaceutical SciencesSchool of Life ScienceNanjing UniversityNanjingChina
| |
Collapse
|
|
14
|
Wang Z, Shi D. Research progress on the neutrophil components and their interactions with immune cells in the development of psoriasis. Skin Res Technol 2023; 29:e13404. [PMID: 37522489 PMCID: PMC10339011 DOI: 10.1111/srt.13404] [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: 06/08/2023] [Accepted: 06/21/2023] [Indexed: 08/01/2023]
Abstract
BACKGROUND Psoriasis is an immune-mediated chronic inflammatory disease, and currently it is widely believed that the IL-23/IL-17 axis and Th17 cells play a critical and central role. However, increasing evidence suggests that neutrophils may interact with a variety of immune cells to play an indispensable role in psoriasis. MATERIALS AND METHODS We searched the recent literature on psoriasis and neutrophils through databases such as PubMed and CNKI, and summarized the findings to draw conclusions. RESULTS Neutrophils can promote the development of psoriasis by secreting IL-23, IL-17, and cytokines with TH17 cell chemotaxis. Activated keratinocytes (KCs) can attract and activate neutrophils, induce the formation of neutrophil extracellular traps (NETs). KCs can also expose self-antigens which lead to strong autoimmune reactions. The granule proteins secreted by activated neutrophils can activate IL-36, which converts vulgaris psoriasis to generalized pustular psoriasis (GPP). CONCLUSION The function of neutrophils components and the interaction between neutrophils and immune cells play an essential role in the pathogenesis of psoriasis. The aim is to provide a theoretical basis for the exploration of targeted clinical treatments and fundamental research on the pathogenesis of psoriasis.
Collapse
Affiliation(s)
- Zhenhui Wang
- Shandong University of Traditional Chinese MedicineJinanShandongChina
| | - Dongmei Shi
- Chief Physician, Doctoral Supervisor, Department of Dermatology & Laboratory of Medical MycologyJining No. 1 People's HospitalJiningShandong ProvinceChina
| |
Collapse
|
|
15
|
Carnevale S, Di Ceglie I, Grieco G, Rigatelli A, Bonavita E, Jaillon S. Neutrophil diversity in inflammation and cancer. Front Immunol 2023; 14:1180810. [PMID: 37180120 PMCID: PMC10169606 DOI: 10.3389/fimmu.2023.1180810] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 04/11/2023] [Indexed: 05/15/2023] Open
Abstract
Neutrophils are the most abundant circulating leukocytes in humans and the first immune cells recruited at the site of inflammation. Classically perceived as short-lived effector cells with limited plasticity and diversity, neutrophils are now recognized as highly heterogenous immune cells, which can adapt to various environmental cues. In addition to playing a central role in the host defence, neutrophils are involved in pathological contexts such as inflammatory diseases and cancer. The prevalence of neutrophils in these conditions is usually associated with detrimental inflammatory responses and poor clinical outcomes. However, a beneficial role for neutrophils is emerging in several pathological contexts, including in cancer. Here we will review the current knowledge of neutrophil biology and heterogeneity in steady state and during inflammation, with a focus on the opposing roles of neutrophils in different pathological contexts.
Collapse
Affiliation(s)
| | | | - Giovanna Grieco
- IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | | | | | - Sebastien Jaillon
- IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| |
Collapse
|
|
16
|
Faraoni EY, O'Brien BJ, Strickland LN, Osborn BK, Mota V, Chaney J, Atkins CL, Cen P, Rowe J, Cardenas J, Poulsen KL, Wray CJ, Thosani NC, Bailey-Lundberg JM. Radiofrequency Ablation Remodels the Tumor Microenvironment and Promotes Neutrophil-Mediated Abscopal Immunomodulation in Pancreatic Cancer. Cancer Immunol Res 2023; 11:4-12. [PMID: 36367967 PMCID: PMC9808367 DOI: 10.1158/2326-6066.cir-22-0379] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 09/01/2022] [Accepted: 11/03/2022] [Indexed: 11/13/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) presents a 5-year overall survival rate of 11%, despite efforts to improve clinical outcomes in the past two decades. Therapeutic resistance is a hallmark of this disease, due to its dense and suppressive tumor microenvironment (TME). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a promising local ablative and potential immunomodulatory therapy for PDAC. In this study, we performed RFA in a preclinical tumor-bearing KrasG12D; Trp53R172H/+; Pdx1:Cre (KPC) syngeneic model, analyzed local and abscopal affects after RFA and compared our findings with resected PDAC specimens. We found that RFA reduced PDAC tumor progression in vivo and promoted strong TME remodeling. In addition, we discovered tumor-infiltrating neutrophils determined abscopal effects. Using imaging mass cytometry, we showed that RFA elevated dendritic cell numbers in RFA-treated tumors and promoted a significant CD4+ and CD8+ T-cell abscopal response. In addition, RFA elevated levels of programmed death-ligand 1 (PD-L1) and checkpoint blockade inhibition targeting PD-L1 sustained tumor growth reduction in the context of RFA. This study indicates RFA treatment, which has been shown to increase tumor antigen shedding, promotes antitumor immunity. This is critical in PDAC where recent clinical immunotherapy trials have not resulted in substantial changes in overall survival.
Collapse
Affiliation(s)
- Erika Y. Faraoni
- Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Baylee J. O'Brien
- Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Lincoln N. Strickland
- Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Baron K. Osborn
- Department of Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Victoria Mota
- Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Jarod Chaney
- Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Constance Lynn Atkins
- Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Putao Cen
- Division of Oncology, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Julie Rowe
- Division of Oncology, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Jessica Cardenas
- Department of Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Kyle L. Poulsen
- Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
- Center for Perioperative Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Curtis J. Wray
- Department of Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Nirav C. Thosani
- Center for Interventional Gastroenterology at UTHealth (iGUT), McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Jennifer M. Bailey-Lundberg
- Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
- Center for Perioperative Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
- Center for Interventional Gastroenterology at UTHealth (iGUT), McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| |
Collapse
|
|
17
|
Xu H, Zhao Y, Zhao Q, Shi M, Zhang Z, Ding W, Zhao Y. Tuberous Sclerosis Complex 1 Deficiency in Macrophages Promotes Unclassical Inflammatory Response to Lipopolysaccharide In Vitro and Dextran Sodium Sulfate-Induced Colitis in Mice. Aging Dis 2022; 13:1875-1890. [PMID: 36465179 PMCID: PMC9662278 DOI: 10.14336/ad.2022.0408] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 04/08/2022] [Indexed: 09/01/2023] Open
Abstract
Human tuberous sclerosis (TSC) is mainly caused by genetic mutations of tuberous TSC1or TSC2. Recent studies found that TSC1 deficiency promoted classical M1 macrophage polarization. However, whether TSC1 regulates other inflammatory cytokine expression in lipopolysaccharidem (LPS)-stimulated macrophages is unknown. Herein, we studied the cytokine expression profile of wild-type (WT) and TSC1-deleted macrophages after LPS stimulation in vitro and the pathogenesis of dextran sodium sulfate (DSS)-induced colitis in mice with myeloid-specific TSC1 deletion (TSC1cKO mice). We found that TSC1-deficient macrophages exhibited the enhanced secretion of interleukin-17A (IL-17A), IL-17F, and interferon-gamma (IFN-γ) in response to LPS stimulation in vitro. This is in contrast to LPS-stimulated WT macrophages, which usually do not. Importantly, TSC1cKO mice exhibited exacerbated DSS-induced acute colitis with severer symptoms. MTOR deletion or rapamycin treatment significantly reversed the enhanced expressions of IL-17A, IL-17F, and IFN-γ in LPS-stimulated TSC1-deficient macrophages in vitro and rescued the enhanced DSS-induced colitis in TSC1cKO mice, indicating that TSC1 deficiency increased these cytokine productions in an mTOR-dependent manner. RNA-sequencing and molecular studies indicated that TSC1 deficiency enhanced the aerobic glycolysis process and the activities of mTOR-STAT3-RORγT pathway in LPS-stimulated macrophages. Inhibition of aerobic glycolysis, STAT3, or RORγT reversed IL-17 and IFN-γ expression in LPS-treated TSC1-deficient macrophages. Thus, TSC1 is essential for macrophages to shut down IL-17A, IL-17F, and IFN-γ expression during LPS stimulation by suppressing the aerobic glycolysis process and mTOR-STAT3, RORγT, and T-bet pathways. The present study uncovered the key role of TSC1 in shutting down IL-17A, IL-17F, and IFN-γ expressions in LPS-treated macrophages.
Collapse
Affiliation(s)
- Huawen Xu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- Cunji Medical College, University of Chinese Academy of Sciences, Beijing, China.
| | - Yang Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- Cunji Medical College, University of Chinese Academy of Sciences, Beijing, China.
| | - Qingjie Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
| | - Mingpu Shi
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- Cunji Medical College, University of Chinese Academy of Sciences, Beijing, China.
| | - Zhaoqi Zhang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- Cunji Medical College, University of Chinese Academy of Sciences, Beijing, China.
| | - Wenjun Ding
- Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- Cunji Medical College, University of Chinese Academy of Sciences, Beijing, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
| |
Collapse
|
|
18
|
Guo H, Bossila EA, Ma X, Zhao C, Zhao Y. Dual Immune Regulatory Roles of Interleukin-33 in Pathological Conditions. Cells 2022; 11:cells11203237. [PMID: 36291105 PMCID: PMC9600220 DOI: 10.3390/cells11203237] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/07/2022] [Accepted: 10/11/2022] [Indexed: 11/20/2022] Open
Abstract
Interleukin-33 (IL-33), a member of the IL-1 cytokine family and a multifunctional cytokine, plays critical roles in maintaining host homeostasis and in pathological conditions, such as allergy, infectious diseases, and cancer, by acting on multiple types of immune cells and promoting type 1 and 2 immune responses. IL-33 is rapidly released by immune and non-immune cells upon stimulation by stress, acting as an “alarmin” by binding to its receptor, suppression of tumorigenicity 2 (ST2), to trigger downstream signaling pathways and activate inflammatory and immune responses. It has been recognized that IL-33 displays dual-functioning immune regulatory effects in many diseases and has both pro- and anti-tumorigenic effects, likely depending on its primary target cells, IL-33/sST2 expression levels, cellular context, and the cytokine microenvironment. Herein, we summarize our current understanding of the biological functions of IL-33 and its roles in the pathogenesis of various conditions, including inflammatory and autoimmune diseases, infections, cancers, and cases of organ transplantation. We emphasize the nature of context-dependent dual immune regulatory functions of IL-33 in many cells and diseases and review systemic studies to understand the distinct roles of IL-33 in different cells, which is essential to the development of more effective diagnoses and therapeutic approaches for IL-33-related diseases.
Collapse
Affiliation(s)
- Han Guo
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
| | - Elhusseny A. Bossila
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
- Biotechnology Department, Faculty of Agriculture Al-Azhar University, Cairo 11311, Egypt
| | - Xinran Ma
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
| | - Chenxu Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
- Beijing Institute for Stem Cell and Regeneration, Beijing 100101, China
- Correspondence: ; Tel.: +86-10-64807302; Fax: +86-10-64807313
| |
Collapse
|
|
19
|
Ding F, Han L, Fu Q, Fan X, Tang R, Lv C, Xue Y, Tian X, Zhang M. IL-17 Aggravates Pseudomonas aeruginosa Airway Infection in Acute Exacerbations of Chronic Obstructive Pulmonary Disease. Front Immunol 2022; 12:811803. [PMID: 35095906 PMCID: PMC8792752 DOI: 10.3389/fimmu.2021.811803] [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] [Received: 11/09/2021] [Accepted: 12/22/2021] [Indexed: 01/02/2023] Open
Abstract
Pseudomonas aeruginosa airway infection increases risks of exacerbations and mortality in chronic obstructive pulmonary disease (COPD). We aimed to elucidate the role of IL-17 in the pathogenesis. We examined the expression and influences of IL-23/IL-17A in patients with stable COPD (n = 33) or acute COPD exacerbations with P. aeruginosa infection (n = 34). A mouse model of COPD (C57BL/6) was used to investigate the role of IL-17A in host inflammatory responses against P. aeruginosa infection through the application of IL-17A–neutralizing antibody or recombinant IL-17A. We found that P. aeruginosa infection increased IL-23/17A signaling in lungs of both COPD patients and COPD mouse models. When COPD mouse models were treated with neutralizing antibody targeting IL-17A, P. aeruginosa induced a significantly less polymorphonuclear leukocyte infiltration and less bacterial burden in their lungs compared to those of untreated counterparts. The lung function was also improved by neutralizing antibody. Furthermore, IL-17A-signaling blockade significantly reduced the expression of pro-inflammatory cytokine IL-1β, IL-18, TNF-α, CXCL1, CXCL15 and MMP-9, and increased the expression of anti-inflammatory cytokine IL-10 and IL-1Ra. The application of mouse recombinant IL-17A exacerbated P. aeruginosa-mediated inflammatory responses and pulmonary dysfunction in COPD mouse models. A cytokine protein array revealed that the expression of retinol binding protein 4 (RBP4) was down-regulated by IL-17A, and exogenous RBP4-recombinant protein resulted in a decrease in the severity of P. aeruginosa-induced airway dysfunction. Concurrent application of IL-17A-neutralizing antibody and ciprofloxacin attenuated airway inflammation and ventilation after inoculation of P. aeruginosa in COPD mouse models. Our results revealed that IL-17 plays a detrimental role in the pathogenesis of P. aeruginosa airway infection during acute exacerbations of COPD. Targeting IL-17A is a potential therapeutic strategy in controlling the outcomes of P. aeruginosa infection in COPD patients.
Collapse
Affiliation(s)
- Fengming Ding
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Han
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiang Fu
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinxin Fan
- Department of Tuberculosis, Fuzhou Pulmonary Hospital of Fujian Province, Fuzhou, China
| | - Rong Tang
- Department of Clinical Laboratory, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chengjian Lv
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yishu Xue
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xue Tian
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Zhang
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
20
|
Tian Q, Zhang Z, Tan L, Yang F, Xu Y, Guo Y, Wei D, Wu C, Cao P, Ji J, Wang W, Xie X, Zhao Y. Skin and heart allograft rejection solely by long-lived alloreactive T RM cells in skin of severe combined immunodeficient mice. SCIENCE ADVANCES 2022; 8:eabk0270. [PMID: 35080985 PMCID: PMC8791614 DOI: 10.1126/sciadv.abk0270] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Whether induced tissue-resident memory T (TRM) cells in nonlymphoid organs alone can mediate allograft rejection is unknown. By grafting alloskin or heart into severe combined immunodeficient or Rag2KO mice in which a piece of induced CD4+ and/or CD8+ TRM cell-containing MHC-matched or syngeneic skin was transplanted in advance, we addressed this issue. The induced CD4+ TRM cells in the skin alone acutely rejected alloskin or heart grafts. RNA-seq analysis showed that induced CD4+ TRM cells in skin favorably differentiated into TH17-like polarization during the secondary immune response. Inhibition of the key TH17 signaling molecule RORγt attenuated TRM cell-mediated graft rejection. Thus, we offer a unique mouse model to specifically study TRM cell-mediated allograft rejection without the involvement of lymphocytes in lymphoid organs and tissues. Our study provides strong evidence supporting the hypothesis that long-lived alloreactive TRM cells resident in other organs/tissues substantially contribute to organ allograft rejection.
Collapse
Affiliation(s)
- Qianchuan Tian
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Zhaoqi Zhang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Liang Tan
- Department of Urological Organ Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Fan Yang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yanan Xu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yinan Guo
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Dong Wei
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Changhong Wu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Peng Cao
- Department of Urology, Capital Medical University Beijing Chaoyang Hospital, Beijing, China
| | - Jiawei Ji
- Department of Urology, Capital Medical University Beijing Chaoyang Hospital, Beijing, China
| | - Wei Wang
- Department of Urology, Capital Medical University Beijing Chaoyang Hospital, Beijing, China
- Corresponding author. (Y.Z.); (X.X.); (W.W.)
| | - Xubiao Xie
- Department of Urological Organ Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Corresponding author. (Y.Z.); (X.X.); (W.W.)
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Corresponding author. (Y.Z.); (X.X.); (W.W.)
| |
Collapse
|
|
21
|
Mosca M, Hong J, Hadeler E, Hakimi M, Liao W, Bhutani T. The Role of IL-17 Cytokines in Psoriasis. Immunotargets Ther 2021; 10:409-418. [PMID: 34853779 PMCID: PMC8627853 DOI: 10.2147/itt.s240891] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 10/22/2021] [Indexed: 12/18/2022] Open
Abstract
Psoriasis is a chronic inflammatory skin condition associated with immune dysregulation. The immunologic cascade mediated by the interleukin (IL)-17 pathway plays a critically important role in the pathogenesis of psoriasis. The IL-17 effectors (IL-17A, IL-17C, IL-17E, and IL17F) act on keratinocytes, endothelial cells, and immune cells to stimulate epidermal hyperplasia and the pro-inflammatory feed-forward cycle seen within plaque psoriasis. The IL-17 pathway is also hypothesized to modulate the inflammatory responses linking comorbid systemic diseases with psoriasis. Furthermore, the robust clinical response seen with current and emerging therapies targeting IL-17 emphasizes the importance of the IL-17 cytokines in the pathogenesis of psoriasis.
Collapse
Affiliation(s)
- Megan Mosca
- Psoriasis and Skin Treatment Center, Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Julie Hong
- Psoriasis and Skin Treatment Center, Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Edward Hadeler
- Psoriasis and Skin Treatment Center, Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Marwa Hakimi
- Psoriasis and Skin Treatment Center, Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Wilson Liao
- Psoriasis and Skin Treatment Center, Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Tina Bhutani
- Psoriasis and Skin Treatment Center, Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| |
Collapse
|
|
22
|
Chen Y, Li Y, Guo H, Zhang Z, Zhang J, Dong X, Liu Y, Zhuang Y, Zhao Y. The Effects of Adoptively Transferred IL-23/IL-18-Polarized Neutrophils on Tumor and Collagen-Induced Arthritis in Mice. J Inflamm Res 2021; 14:4669-4686. [PMID: 34557012 PMCID: PMC8453247 DOI: 10.2147/jir.s329528] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 09/04/2021] [Indexed: 12/04/2022] Open
Abstract
Background Neutrophils present great diverse phenotypes in various microenvironments and play different immune regulatory functions. Neutrophils generally classified into inflammatory phenotype N1 and anti-informatory phenotype N2. Our recent studies showed that IL-23 alone stimulated neutrophils to express IL-17A, IL-17F and IL-22 and displayed a gene transcriptional profile similar to Th17 cells. In the present study, we tried to identify potential cytokines to promote IL-23-induced neutrophil polarization. Methods Mouse bone marrow-derived neutrophils and human peripheral blood neutrophils were treated with IL-23 (10 ng/mL) plus IL-18 (25 ng/mL) to induce Th17-like subset in vitro and detected by real-time PCR, flow cytometry, ELISA, immunofluorescence and RNA-seq assays. In vivo, collagen-induced arthritis (CIA) mouse model and EL4 tumor-bearing mouse model were used to characterize the potential roles of N(IL-23+IL-18) in inflammation and tumor. Results Real-time PCR, ELISA and flow cytometry assays showed that IL-18 could significantly enhance IL-23-induced IL-17A, IL-17F and IL-22 expressions in mouse and human neutrophils in a synergistic way, although IL-18 alone failed to induce these cytokines expression. RNA-seq and molecular studies showed that the polarization of N(IL-23+IL-18) is mainly mediated by the JNK/p38-STAT3-BATF signaling pathway. Adoptive transfer of the induced N(IL-23+IL-18) neutrophils significantly accelerated the tumor growth in EL4 tumor-bearing mice and enhanced disease progression in the CIA mouse model. IL-17A-deficient N(IL-23+IL-18) neutrophils failed to enhance the CIA pathogenesis in this model, suggesting that IL-17A may be involved in the N(IL-23+IL-18) neutrophils-promoted arthritis in mice. Conclusion The Th17-type subpopulation N(IL-23+IL-18) has pro-tumor and pro-inflammatory properties. Recognizing the different functional polarization of neutrophils would significantly help us to understand the distinctive protective/pathological roles of neutrophils in physiological and different pathological situations.
Collapse
Affiliation(s)
- Yifang Chen
- Department of State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Yang Li
- Department of State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Han Guo
- Department of State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China.,Savaid Medical School, University of Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Zhaoqi Zhang
- Department of State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China.,Savaid Medical School, University of Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Jiayu Zhang
- Department of State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China.,Savaid Medical School, University of Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Xue Dong
- Department of State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Yi Liu
- Department of Blood Transfusion, First Medical Center of Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Yuan Zhuang
- Department of Blood Transfusion, First Medical Center of Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Yong Zhao
- Department of State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China.,Department of State Key Laboratory of Membrane Biology, Institute for Stem Cell and Regeneration, Chinese Academy of Science, Beijing, People's Republic of China
| |
Collapse
|
|
23
|
Charitidis FT, Damlund DSM, Koch J. Psoriasis-like Inflammation Induced in an Air-pouch Mouse Model. In Vivo 2021; 35:1985-1997. [PMID: 34182473 DOI: 10.21873/invivo.12467] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 04/16/2021] [Accepted: 04/22/2021] [Indexed: 01/31/2023]
Abstract
BACKGROUND/AIM The pathway of initiation of psoriasis comprises the differentiation and infiltration of T-helper 17 (Th17) cells into the skin, characterized by the production of interleukin 17A and 17F (IL-17A/IL-17F) among other cytokines, resulting in a downstream cascade of events. Due to the lack of simplicity in psoriasis models, we aimed to develop an easily and rapidly inducible mouse model for the IL-23/IL-17 pathway with quick readouts from a straightforward lavaging process and with detectable cytokine levels. MATERIALS AND METHODS We utilized the 6-day air-pouch mouse model, injected with a combination of anti-CD3, IL-23 and IL-1β. At 24, 48 and 72 h, intra-pouch secretion of IL-17A, IL-17F and C-X-C motif chemokine ligand 1 were measured. Skin biopsies were collected and immune cell infiltration evaluated, and intra-pouch immune cells were isolated and analyzed. RESULTS The combination of anti-CD3, IL-23 with and without IL-1β significantly increased intra-pouch levels of IL-17A/IL-17F at 24 and 72 h, triggering a downstream production of C-X-C motif chemokine ligand 1. The cytokines were detectable even 72 h post-induction. T-cell receptor beta was down-regulated on CD4+ and CD8+ T-cells, indicating intra-pouch T-cell activation. Αnti-CD3 induced CD3+ cell migration into the subcutis and the lining tissue surrounding the cavity of the air pouch, where in the latter, a similar distribution pattern of Il17a mRNA-expressing cells was also observed. However, no Th17 cell differentiation nor changes in IL-17A+ granulocytes were observed. CONCLUSION The induced air-pouch mouse model induced with a cocktail of anti-CD3, IL-23 with or without IL-1β is able to mirror the IL-23/IL-17 axis of psoriasis-like inflammation characterized by immune cell infiltration and cytokine secretion.
Collapse
Affiliation(s)
| | - Dina S M Damlund
- Department of In Vivo Biology & Safety, LEO Pharma A/S, Ballerup, Denmark
| | - Janne Koch
- Department of In Vivo Biology & Safety, LEO Pharma A/S, Ballerup, Denmark
| |
Collapse
|
|
24
|
Shi L, Tian Q, Feng C, Zhang P, Zhao Y. The biological function and the regulatory roles of wild-type p53-induced phosphatase 1 in immune system. Int Rev Immunol 2020; 39:280-291. [PMID: 32696682 DOI: 10.1080/08830185.2020.1795153] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Wild-type p53-induced phosphatase 1 (WIP1) belongs to the protein phosphatase 2C (PP2C) family and is a mammalian serine/threonine specific protein phosphatase to dephosphorylate numerous signaling molecules. Mammalian WIP1 regulates a wide array of targeting molecules and plays key regulatory roles in many cell processes such as DNA damage and repair, cell proliferation, differentiation, apoptosis, and senescence. WIP1 promotes the formation and development of tumors as an oncogene and a negative regulator of p53. It is also involved in the regulation of aging, neurological diseases and immune diseases. Recent studies demonstrated the critical roles of WIP1 in the differentiation and function of immune cells including T cells, neutrophils and macrophages. In the present manuscript, we briefly summarized the expression patterns, biological function and the target molecules and signal pathways of WIP1 and mainly discussed the latest advances on the regulatory effects of WIP1 in the immune system. WIP1 may be a potential target molecule to treat cancers and immune diseases such as allergic asthma.
Collapse
Affiliation(s)
- Lu Shi
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Qianchuan Tian
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Chang Feng
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Peng Zhang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| |
Collapse
|
|
25
|
Delli FS, Sotiriou E, Lazaridou E, Apalla Z, Lallas A, Vakirlis E, Gerou S, Bougioukas K, Ioannides D. Total IgE, eosinophils, and interleukins 16, 17A, and 23 correlations in severe bullous pemphigoid and treatment implications. Dermatol Ther 2020; 33:e13958. [PMID: 32621642 DOI: 10.1111/dth.13958] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 06/15/2020] [Accepted: 06/30/2020] [Indexed: 12/13/2022]
Abstract
Bullous pemphigoid (BP) patients are predominantly above 70 years of age, with limited tolerance to the side effects of the immunosuppressive drugs. Advancements in our understanding of the pathophysiology of BP have led to the development of molecules which target specific pathways involved in induction and perpetuation of disease. Patients with BP Disease Area Index above 60 and less than 100 were split into two groups-one with high and the other with normal levels of IgE. The tested parameters included eosinophils' count, total IgE serum level, and interleukins (IL) 16, 17A, and 23 counts in the peripheral blood and skin bulla serum, before any therapeutic intervention. Thirty individuals fulfilled the criteria for enrollment. Patients with high IgE blood serum levels had significantly higher levels of IL17A and normal IL23 levels in blood and bulla serum. Patients with normal serum IgE levels had slightly higher IL23 levels in blood and bulla serum. The eosinophil count was positively related to IL17 blood serum level and negatively related to IL23. IL16 did not differ in the two groups. BP patients may represent a group of patients benefiting most substantially from the introduction of nonimmunosuppressive therapeutics into the treatment regimens for their disease. Clinical criteria and immune biomarkers are needed for making the best therapeutic choice.
Collapse
Affiliation(s)
| | - Elena Sotiriou
- First Dermatology Department, Aristotle University of Medical School, Thessaloniki, Greece
| | - Elizabeth Lazaridou
- Second Dermatology Department, Aristotle University of Medical School, Thessaloniki, Greece
| | - Zoe Apalla
- Second Dermatology Department, Aristotle University of Medical School, Thessaloniki, Greece
| | - Aimilios Lallas
- First Dermatology Department, Aristotle University of Medical School, Thessaloniki, Greece
| | - Efstratios Vakirlis
- First Dermatology Department, Aristotle University of Medical School, Thessaloniki, Greece
| | - Spyros Gerou
- Department of Microbiology, Aristotle University of Medical School, Thessaloniki, Greece
| | - Konstantinos Bougioukas
- Department of Hygiene, Social-Preventive Medicine & Medical Statistics, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Demetrios Ioannides
- First Dermatology Department, Aristotle University of Medical School, Thessaloniki, Greece
| |
Collapse
|
|
26
|
Chu Z, Sun C, Sun L, Feng C, Yang F, Xu Y, Zhao Y. Primed macrophages directly and specifically reject allografts. Cell Mol Immunol 2020; 17:237-246. [PMID: 30948792 PMCID: PMC7052205 DOI: 10.1038/s41423-019-0226-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 03/10/2019] [Indexed: 11/09/2022] Open
Abstract
Monocytes and macrophages have long been associated with acute and chronic allograft rejection; this is mediated by their abilities to promote inflammation, kill target cells via antibody-dependent cytotoxicity and modulate adaptive immunity. Our present study showed that allogeneic antigen-primed macrophages acutely rejected skin grafts with specificity after adoptive transfer into MHC-matched immunodeficient mice. The ability of primed macrophages to reject allografts essentially requires the help of CD4+ T cells and does not require the help of CD8+ T cells. Moreover, the primed, perforin-deficient macrophages rejected the skin grafts in a significantly delayed pattern compared with WT macrophages, indicating that the perforin pathway of the primed macrophages is likely involved in the rejection process. Thus, primed macrophages are endowed with adaptive immunity-like features, such as specificity, with the help of CD4+ T cells during the immune response to allografts. The present study challenges our traditional views of macrophage functions and highlights the biological functions of macrophages beyond innate immunity in mammals.
Collapse
Grants
- This work was supported by grants from the National Key R&D Program of China (2017YFA0105002, 2017YFA0104402, Y.Z.), National Science and Technology Major Project (2017ZX10201101), the National Natural Science Foundation for General and Key Programs (C81530049, C81130055, C31470860, Y.Z.), Knowledge Innovation Program of Chinese Academy of Sciences (XDA04020202-19, Y.Z.), and the China Manned Space Flight Technology Project (TZ-1, Y.Z.).
Collapse
Affiliation(s)
- Zhulang Chu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Chenming Sun
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Lina Sun
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Chang Feng
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Fan Yang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yanan Xu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
| |
Collapse
|
|
27
|
Xu Y, Zhang Q, Zhao Y. The functional diversity of neutrophils and clustered polarization of immunity. Cell Mol Immunol 2020; 17:1212-1214. [PMID: 32094506 DOI: 10.1038/s41423-020-0378-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 02/06/2020] [Indexed: 02/03/2023] Open
Affiliation(s)
- Yanan Xu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Qian Zhang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. .,University of Chinese Academy of Sciences, Beijing, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
| |
Collapse
|
|
28
|
Nur S, Sparber F, Lemberg C, Guiducci E, Schweizer TA, Zwicky P, Becher B, LeibundGut-Landmann S. IL-23 supports host defense against systemic Candida albicans infection by ensuring myeloid cell survival. PLoS Pathog 2019; 15:e1008115. [PMID: 31887131 PMCID: PMC6957211 DOI: 10.1371/journal.ppat.1008115] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 01/13/2020] [Accepted: 10/01/2019] [Indexed: 01/21/2023] Open
Abstract
The opportunistic fungal pathogen Candida albicans can cause invasive infections in susceptible hosts and the innate immune system, in particular myeloid cell-mediated immunity, is critical for rapid immune protection and host survival during systemic candidiasis. Using a mouse model of the human disease, we identified a novel role of IL-23 in antifungal defense. IL-23-deficient mice are highly susceptible to systemic infection with C. albicans. We found that this results from a drastic reduction in all subsets of myeloid cells in the infected kidney, which in turn leads to rapid fungal overgrowth and renal tissue injury. The loss in myeloid cells is not due to a defect in emergency myelopoiesis or the recruitment of newly generated cells to the site of infection but, rather, is a consequence of impaired survival of myeloid cells at the site of infection. In fact, the absence of a functional IL-23 pathway causes massive myeloid cell apoptosis upon C. albicans infection. Importantly, IL-23 protects myeloid cells from apoptosis independently of the IL-23-IL-17 immune axis and independently of lymphocytes and innate lymphoid cells. Instead, our results suggest that IL-23 acts in a partially autocrine but not cell-intrinsic manner within the myeloid compartment to promote host protection from systemic candidiasis. Collectively, our data highlight an unprecedented and non-canonical role of IL-23 in securing survival of myeloid cells, which is key for maintaining sufficient numbers of cells at the site of infection to ensure efficient host protection. Linked to advances in medical technology and the resulting increase in the number of intensive care patients, nosocomial infections with Candida albicans are on the rise. In patients suffering from invasive candidiasis the innate immune response is typically severely impaired. Strengthening the innate immune system has become a promising approach complementing the use of antifungal drugs. Our findings identify an unexpected and IL-17-independent role of IL-23 that prevents rapid death of myeloid cells during systemic candidiasis and thereby promotes optimal protection from disease. As such, IL-23 represents an important new piece in the puzzle of the finely tuned network of cytokines that regulates the innate immune response to fungal infection. Our results contribute to a better understanding of myeloid cell regulation during infection and thereby open new perspectives for future immunotherapeutic applications that may improve patient outcome.
Collapse
Affiliation(s)
- Selim Nur
- Section of Immunology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
| | - Florian Sparber
- Section of Immunology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
| | - Christina Lemberg
- Section of Immunology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
| | - Eva Guiducci
- Section of Immunology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
| | - Tiziano A. Schweizer
- Section of Immunology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
| | - Pascale Zwicky
- Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland
| | - Burkhard Becher
- Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland
| | | |
Collapse
|
|
29
|
Me R, Gao N, Dai C, Yu FSX. IL-17 Promotes Pseudomonas aeruginosa Keratitis in C57BL/6 Mouse Corneas. THE JOURNAL OF IMMUNOLOGY 2019; 204:169-179. [PMID: 31767781 DOI: 10.4049/jimmunol.1900736] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 10/30/2019] [Indexed: 12/11/2022]
Abstract
The aim of this study was to elucidate the expression and functions of IL-17 in C57BL/6 mouse corneas in response to Pseudomonas aeruginosa infection. We found that P. aeruginosa infection induced and increased signaling of IL-23/23R/17/17R in mouse corneas. Targeting IL-17A or the IL-17A-specific receptor IL-17RA/IL-17RC with neutralizing Abs resulted in a significant decrease in the severity of P. aeruginosa keratitis, including a decrease in bacterial burden and polymorphonuclear leukocyte infiltration. IL-17A-signaling blockade also significantly reduced the expression of the proinflammatory cytokines L-1β, IL-24, and MMP-13 and increased the expression of the anti-inflammatory cytokine IL-1RA in mouse corneal epithelium. The presence of mouse IL-17A exacerbated P. aeruginosa-mediated tissue destruction. A cytokine protein array revealed that the expression of osteoprotegerin (OPG) was regulated by IL-17A, and OPG neutralization also resulted in a decrease in the severity of P. aeruginosa keratitis. Although both IL-17 and OPG affected the balanced expression of IL-1β and IL-1RA, only IL-17 inhibited the expression of TH2 cytokines. Taken together, our results revealed that IL-17A, along with its downstream factor OPG, plays a detrimental role in the pathogenesis of P. aeruginosa keratitis. Targeting IL-17A and/or the OPG/RANKL/RANK/TRAIL system is a potential therapeutic strategy in controlling the outcome of P. aeruginosa keratitis, which was demonstrated by concurrent topical application of IL-17A-neutralizing Ab and ciprofloxacin in B6 mice.
Collapse
Affiliation(s)
- Rao Me
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201.,Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI 48201; and
| | - Nan Gao
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201.,Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI 48201; and
| | - Chenyang Dai
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201.,Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI 48201; and.,Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong, China 250014
| | - Fu-Shin X Yu
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201; .,Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI 48201; and
| |
Collapse
|
|
30
|
Li Y, Wang W, Yang F, Xu Y, Feng C, Zhao Y. The regulatory roles of neutrophils in adaptive immunity. Cell Commun Signal 2019; 17:147. [PMID: 31727175 PMCID: PMC6854633 DOI: 10.1186/s12964-019-0471-y] [Citation(s) in RCA: 156] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 10/25/2019] [Indexed: 12/16/2022] Open
Abstract
Neutrophils have long been considered as cells playing a crucial role in the immune defence against invading pathogens. Accumulating evidence strongly supported the direct and indirect regulatory effects of neutrophils on adaptive immunity. Exogenous cytokines or cytokines produced in an autocrine manner as well as a cell-to-cell contact between neutrophils and T cells could induce the expression of MHC-II and costimulatory molecules on neutrophils, supporting that neutrophils may function as antigen-presenting cells (APCs) in respects of presenting antigens and activating T cells. In addition to the inflammatory roles, neutrophils also have the propensity and ability to suppress the immune response through different mechanisms. In this review, we will mainly highlight the heterogeneity and functional plasticity of neutrophils and the antigen-presenting capacity of different neutrophil subsets. We also discuss mechanisms relevant to the regulatory effects of neutrophils on adaptive immunity. Understanding how neutrophils modulate adaptive immunity may provide novel strategies and new therapeutic approaches for diseases associated with neutrophils.
Collapse
Affiliation(s)
- Yang Li
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beichen West Road 1-5, Chaoyang District, Beijing, 100101, China
| | - Wei Wang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Fan Yang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beichen West Road 1-5, Chaoyang District, Beijing, 100101, China
| | - Yanan Xu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beichen West Road 1-5, Chaoyang District, Beijing, 100101, China
| | - Chang Feng
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beichen West Road 1-5, Chaoyang District, Beijing, 100101, China
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beichen West Road 1-5, Chaoyang District, Beijing, 100101, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
| |
Collapse
|
|
31
|
Chen L, Shen Z. Tissue-resident memory T cells and their biological characteristics in the recurrence of inflammatory skin disorders. Cell Mol Immunol 2019; 17:64-75. [PMID: 31595056 DOI: 10.1038/s41423-019-0291-4] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 08/25/2019] [Indexed: 11/09/2022] Open
Abstract
The skin is the largest organ of the body. The establishment of immunological memory in the skin is a crucial component of the adaptive immune response. Once naive T cells are activated by antigen-presenting cells, a small fraction of them differentiate into precursor memory T cells. These precursor cells ultimately develop into several subsets of memory T cells, including central memory T (TCM) cells, effector memory T (TEM) cells, and tissue resident memory T (TRM) cells. TRM cells have a unique transcriptional profile, and their most striking characteristics are their long-term survival (longevity) and low migration in peripheral tissues, including the skin. Under physiological conditions, TRM cells that reside in the skin can respond rapidly to pathogenic challenges. However, there is emerging evidence to support the vital role of TRM cells in the recurrence of chronic inflammatory skin disorders, including psoriasis, vitiligo, and fixed drug eruption, under pathological or uncontrolled conditions. Clarifying and characterizing the mechanisms that are involved in skin TRM cells will help provide promising strategies for reducing the frequency and magnitude of skin inflammation recurrence. Here, we discuss recent insights into the generation, homing, retention, and survival of TRM cells and share our perspectives on the biological characteristics of TRM cells in the recurrence of inflammatory skin disorders.
Collapse
Affiliation(s)
- Ling Chen
- Department of Dermatology, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Zhu Shen
- Department of Dermatology, Institute of Dermatology and Venereology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital; School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
| |
Collapse
|
|
32
|
Wang P, Xu Y, Zhang J, Shi L, Lei T, Hou Y, Lu Z, Zhao Y. The amino acid sensor general control nonderepressible 2 (GCN2) controls T H9 cells and allergic airway inflammation. J Allergy Clin Immunol 2019; 144:1091-1105. [PMID: 31121187 DOI: 10.1016/j.jaci.2019.04.028] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 04/11/2019] [Accepted: 04/17/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND TH9 cells have emerged as important mediators of allergic airway inflammation. There is evidence that general control nonderepressible 2 (GCN2) affects the immune response under some stress conditions. However, whether GCN2 regulates CD4+ T-cell differentiation during allergic inflammation remains unknown. OBJECTIVE We sought to clarify the regulatory roles of GCN2 in CD4+ T-cell subset differentiation and its significance in patients with allergic airway inflammation. METHODS The effects of GCN2 in differentiation of TH cell subsets were detected by using the in vitro induction system. GCN2 knockout mice, ovalbumin-induced allergic airway inflammation, and adoptive transfer mouse models were used to determine the significance of GCN2 in TH9 differentiation and allergic airway inflammation in vivo. RNA sequencing, real-time PCR, Western blotting, and other molecular approaches were used to identify the molecular mechanisms relevant to regulation of GCN2 in TH9 cell differentiation. RESULTS GCN2 deficiency significantly inhibited differentiation of TH9 cells but not TH1, TH2, and regulatory T cells. GCN2 knockout mice and recombination-activating gene 2 knockout (Rag2KO) mice that received adoptively transferred GCN2-deficient CD4+ T cells exhibited reduced TH9 differentiation and less severe allergic airway inflammation. Furthermore, the isolated GCN2-deficient TH9 cells also mediated less severe allergic airway inflammation on adoptive transfer. Mechanistically, GCN2 deficiency inhibits TH9 cell differentiation through a hypoxia-inducible factor 1α-dependent glycolytic pathway. CONCLUSION Our results reveal a novel role of GCN2 in TH9 cell differentiation. Our findings indicate that new strategies to inhibit GCN2 activity might provide novel approaches to attenuate allergic airway inflammation.
Collapse
Affiliation(s)
- Peng Wang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China; Department of Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yana Xu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Jiayu Zhang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Lu Shi
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Tong Lei
- University of Chinese Academy of Sciences, Beijing, China
| | - Yangxiao Hou
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Zhongbing Lu
- University of Chinese Academy of Sciences, Beijing, China.
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
| |
Collapse
|
|
33
|
Wang P, Tian H, Zhang J, Qian J, Li L, Shi L, Zhao Y. Spaceflight/microgravity inhibits the proliferation of hematopoietic stem cells by decreasing Kit-Ras/cAMP-CREB pathway networks as evidenced by RNA-Seq assays. FASEB J 2019; 33:5903-5913. [PMID: 30721627 DOI: 10.1096/fj.201802413r] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Exposure to spaceflight and microgravity causes physiologic and psychologic changes including bone loss, cardiovascular dysfunction, and immune dysfunction. Anemia and hematopoietic disorders are observed in astronauts after spaceflight. Hematopoietic stem and progenitor cells (HSPCs), which can self-renew and give rise to all blood cells, play vital roles in hematopoiesis and homeostasis; however, the molecular mechanisms responsible for the impacts of microgravity on the proliferation of HSPCs remain unclear. We maintained mouse bone marrow HSPCs in the presence of stem cell factor for 12 d under spaceflight and simulated microgravity conditions, respectively, and analyzed cell proliferation and gene expression. Both spaceflight and simulated microgravity significantly decreased the number of HSPCs, mainly by blocking cell cycle at G1/S transition, but did not affect their differentiation abilities. RNA-sequencing data indicated that genes related to cell proliferation were down-regulated, whereas the genes related to cell death were up-regulated under microgravity. Among the gene signatures, we identified that the Kit-Ras/cAMP-cAMP response element-binding protein pathway might be one of the major microgravity-regulated pathways during HSPC proliferation. Furthermore, the quantification of notable genes was validated at the mRNA levels under simulated microgravity condition. Overall, these results would help us to understand the intracellular molecular mechanisms regulating microgravity-inhibited proliferation of HSPCs.-Wang, P., Tian, H., Zhang, J., Qian, J., Li, L., Shi, L., Zhao, Y. Spaceflight/microgravity inhibits the proliferation of hematopoietic stem cells by decreasing Kit-Ras/cAMP-CREB pathway networks as evidenced by RNA-Seq assays.
Collapse
Affiliation(s)
- Peng Wang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Hongling Tian
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Jiayu Zhang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Juanjuan Qian
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Ling Li
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Lu Shi
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| |
Collapse
|
|
34
|
Sun B, Zhu L, Tao Y, Sun HX, Li Y, Wang P, Hou Y, Zhao Y, Zhang X, Zhang L, Na N, Zhao Y. Characterization and allergic role of IL-33-induced neutrophil polarization. Cell Mol Immunol 2018; 15:782-793. [PMID: 29503441 PMCID: PMC6141612 DOI: 10.1038/cmi.2017.163] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 12/11/2017] [Accepted: 12/11/2017] [Indexed: 01/09/2023] Open
Abstract
Neutrophils are involved in the pathogenesis of allergy. However, the contribution of the different functionally polarized neutrophils in allergy needs to be clarified. We sought to define the characteristics of interleukin (IL)-33-induced neutrophils and the involvement of this subset of polarized neutrophils in allergic pathogenesis. Freshly isolated neutrophils were treated with different cytokines and the cytokine expression levels were detected by real-time PCR. The gene expression profile of IL-33-induced neutrophils was determined by microarray assay. Adoptive transfer assay was used to investigate the function of IL-33-induced neutrophils in an ovalbumin (OVA)-induced allergic asthma model. IL-33-treated neutrophils selectively produced IL-4, IL-5, IL-9 and IL-13 (referred as to N(IL-33) cells) and displayed a distinctive gene expression profile in sharp contrast to resting and lipopolysaccharide (LPS)-treated neutrophils. IL-33-induced neutrophils expressed high Levels of IL-1R2 on cell surface, whereas resting and LPS-treated neutrophils did not, indicating IL-1R2 might be used as a biomarker for N(IL-33) cells. Importantly, N(IL-33) neutrophils exist in the lungs of OVA-induced allergic asthma mice. Adoptive transfer of N(IL-33) neutrophils significantly promotes the severity of the lung pathogenesis in this model. IL-33 induces neutrophil polarization through c-Jun N-terminal kinase- and nuclear factor-κB-dependent pathways. A previously unappreciated neutrophil polarization driven by IL-33 with unique cell surface markers and cytokine/chemokine-producing gene profile was defined. The newly identified N(IL-33) subpopulation may have significant contribution to IL-33-related pathogenesis.
Collapse
Affiliation(s)
- Bo Sun
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China
| | - Linnan Zhu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China
| | - Yaling Tao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China
| | - Hai-Xi Sun
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China
| | - Yang Li
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China
| | - Peng Wang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China
| | - Yuzhu Hou
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China
| | - Yang Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China
| | - Xiaodong Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100101, China
| | - Lianfeng Zhang
- Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
| | - Ning Na
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, Guangdong, China.
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China.
| |
Collapse
|
|
35
|
Kwon OC, Lee EJ, Chang EJ, Youn J, Ghang B, Hong S, Lee CK, Yoo B, Kim YG. IL-17A +GM-CSF + Neutrophils Are the Major Infiltrating Cells in Interstitial Lung Disease in an Autoimmune Arthritis Model. Front Immunol 2018; 9:1544. [PMID: 30013577 PMCID: PMC6036238 DOI: 10.3389/fimmu.2018.01544] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 06/21/2018] [Indexed: 11/25/2022] Open
Abstract
Objective To gain a better understanding of the pathogenesis of autoimmune arthritis-associated interstitial lung disease (ILD), we sought to identify the characteristics of lung-infiltrating cells in SKG mice with ILD. Methods We injected curdlan in SKG mice at 8 weeks of age, and identified the presence of ILD by PET-MRI at 20 weeks post-injection and histological analysis at 22 weeks post-injection. Lung-infiltrating cells were examined by flow cytometry. Analysis of serum cytokines by the Luminex multiplex cytokine assay was performed at 14 and 22 weeks post-injection, and cytokine profiles before and after the development of ILD were compared. Opal multiplexed immunofluorescent staining of lung tissue was also performed. Results At 20 weeks post-injection, curdlan-treated SKG mice developed not only arthritis but also lung inflammation combined with fibrosis, which was identified by PET-MRI and histological analysis. The majority of inflammatory cells that accumulated in the lungs of curdlan-treated SKG mice were CD11b+Gr1+ neutrophils, which co-express IL-17A and GM-CSF, rather than TNF-α. Compared with 14 weeks post-injection, serum levels of GM-CSF, MCP1, IL-17A, IL-23, TSLP, and soluble IL-7Rα had increased at 22 weeks post-injection, whereas those of IFN-γ, IL-22, IL-6, and TNF-α remained unchanged. Furthermore, IL-23, CXCL5, IL-17A, and GM-CSF, but not TNF-α, were observed in immunofluorescent-stained lung tissue. Conclusion We found that IL-17A+GM-CSF+ neutrophils represented the major inflammatory cells in the lungs of curdlan-treated SKG mice. In addition, GM-CSF and IL-17A appear to play a more important role than TNF-α in ILD development.
Collapse
Affiliation(s)
- Oh Chan Kwon
- Division of Rheumatology, Department of Medicine, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, South Korea
| | - Eun-Ju Lee
- Division of Rheumatology, Department of Medicine, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, South Korea
| | - Eun-Ju Chang
- Department of Biomedical Science, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, South Korea
| | - Jeehee Youn
- Department of Anatomy and Cell Biology, College of Medicine, Hanyang University, Seoul, South Korea
| | - Byeongzu Ghang
- Division of Rheumatology, Department of Medicine, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, South Korea
| | - Seokchan Hong
- Division of Rheumatology, Department of Medicine, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, South Korea
| | - Chang-Keun Lee
- Division of Rheumatology, Department of Medicine, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, South Korea
| | - Bin Yoo
- Division of Rheumatology, Department of Medicine, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, South Korea
| | - Yong-Gil Kim
- Division of Rheumatology, Department of Medicine, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, South Korea
| |
Collapse
|
|
36
|
Sparber F, Dolowschiak T, Mertens S, Lauener L, Clausen BE, Joller N, Stoitzner P, Tussiwand R, LeibundGut-Landmann S. Langerin+ DCs regulate innate IL-17 production in the oral mucosa during Candida albicans-mediated infection. PLoS Pathog 2018; 14:e1007069. [PMID: 29782555 PMCID: PMC5983869 DOI: 10.1371/journal.ppat.1007069] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 06/01/2018] [Accepted: 05/01/2018] [Indexed: 12/16/2022] Open
Abstract
The opportunistic fungal pathogen Candida albicans frequently causes diseases such as oropharyngeal candidiasis (OPC) in immunocompromised individuals. Although it is well appreciated that the cytokine IL-17 is crucial for protective immunity against OPC, the cellular source and the regulation of this cytokine during infection are still a matter of debate. Here, we directly visualized IL-17 production in the tongue of experimentally infected mice, thereby demonstrating that this key cytokine is expressed by three complementary subsets of CD90+ leukocytes: RAG-dependent αβ and γδ T cells, as well as RAG-independent ILCs. To determine the regulation of IL-17 production at the onset of OPC, we investigated in detail the myeloid compartment of the tongue and found a heterogeneous and dynamic mononuclear phagocyte (MNP) network in the infected tongue that consists of Zbtb46-Langerin- macrophages, Zbtb46+Langerin+ dendritic cells (DCs) and Ly6C+ inflammatory monocytes. Of those, the Langerin+ DC population stands out by its unique capacity to co-produce the cytokines IL-1β, IL-6 and IL-23, all of which promote IL-17 induction in response to C. albicans in the oral mucosa. The critical role of Langerin+ DCs for the innate IL-17 response was confirmed by depletion of this cellular subset in vivo, which compromised IL-17 induction during OPC. In conclusion, our work revealed key regulatory factors and their cellular sources of innate IL-17-dependent antifungal immunity in the oral mucosa.
Collapse
Affiliation(s)
- Florian Sparber
- Section of Immunology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
| | - Tamas Dolowschiak
- Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland
| | - Sarah Mertens
- Section of Immunology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
| | - Laura Lauener
- Section of Immunology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
| | - Björn E. Clausen
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Nicole Joller
- Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland
| | - Patrizia Stoitzner
- Department of Dermatology, Venereology & Allergology, Medical University Innsbruck, Innsbruck, Austria
| | - Roxane Tussiwand
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | | |
Collapse
|
|
37
|
Th17 cell responses in spondyloarthritis. Best Pract Res Clin Rheumatol 2017; 31:777-796. [DOI: 10.1016/j.berh.2018.07.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 07/09/2018] [Accepted: 07/17/2018] [Indexed: 01/01/2023]
|