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1
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Li C, Wei Y, Lei J. Quantitative cancer-immunity cycle modeling for predicting disease progression in advanced metastatic colorectal cancer. NPJ Syst Biol Appl 2025; 11:33. [PMID: 40221414 PMCID: PMC11993626 DOI: 10.1038/s41540-025-00513-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 03/28/2025] [Indexed: 04/14/2025] Open
Abstract
Patients with advanced metastatic colorectal cancer (mCRC) typically exhibit significant interindividual differences in treatment responses and face poor survival outcomes. To systematically analyze the heterogeneous tumor progression and recurrence observed in advanced mCRC patients, we developed a quantitative cancer-immunity cycle (QCIC) model. The QCIC model employs differential equations to capture the biological mechanisms underlying the cancer-immunity cycle and predicts tumor evolution dynamics under various treatment strategies through stochastic computational methods. We introduce the treatment response index (TRI) to quantify disease progression in virtual clinical trials and the death probability function (DPF) to estimate overall survival. Additionally, we investigate the impact of predictive biomarkers on survival prognosis in advanced mCRC patients, identifying tumor-infiltrating CD8+ cytotoxic T lymphocytes (CTLs) as key predictors of disease progression and the tumor-infiltrating CD4+ Th1/Treg ratio as a significant determinant of survival outcomes. This study presents an approach that bridges the gap between diverse clinical data sources and the generation of virtual patient cohorts, providing valuable insights into interindividual treatment variability and survival forecasting in mCRC patients.
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Affiliation(s)
- Chenghang Li
- School of Mathematical Sciences, Tiangong University, Tianjin, 300387, China
| | - Yongchang Wei
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430072, China.
- Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430072, China.
| | - Jinzhi Lei
- School of Mathematical Sciences, Tiangong University, Tianjin, 300387, China.
- Center for Applied Mathematics, Tiangong University, Tianjin, 300387, China.
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2
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Parthasarathy S, Moreno de Lara L, Carrillo-Salinas FJ, Werner A, Borchers A, Iyer V, Vogell A, Fortier JM, Wira CR, Rodriguez-Garcia M. Human genital dendritic cell heterogeneity confers differential rapid response to HIV-1 exposure. Front Immunol 2024; 15:1472656. [PMID: 39524443 PMCID: PMC11543421 DOI: 10.3389/fimmu.2024.1472656] [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: 07/29/2024] [Accepted: 10/03/2024] [Indexed: 11/16/2024] Open
Abstract
Dendritic cells (DCs) play critical roles in HIV pathogenesis and require further investigation in the female genital tract, a main portal of entry for HIV infection. Here we characterized genital DC populations at the single cell level and how DC subsets respond to HIV immediately following exposure. We found that the genital CD11c+HLA-DR+ myeloid population contains three DC subsets (CD1c+ DC2s, CD14+ monocyte-derived DCs and CD14+CD1c+ DC3s) and two monocyte/macrophage populations with distinct functional and phenotypic properties during homeostasis. Following HIV exposure, the antiviral response was dominated by DCs' rapid secretory response, activation of non-classical inflammatory pathways and host restriction factors. Further, we uncovered subset-specific differences in anti-HIV responses. CD14+ DCs were the main population activated by HIV and mediated the secretory antimicrobial response, while CD1c+ DC2s activated inflammasome pathways and IFN responses. Identification of subset-specific responses to HIV immediately after exposure could aid targeted strategies to prevent HIV infection.
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Affiliation(s)
- Siddharth Parthasarathy
- Department of Immunology, Tufts University School of Medicine, Boston, MA, United States
- Immunology Graduate Program, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, United States
| | - Laura Moreno de Lara
- Department of Immunology, Tufts University School of Medicine, Boston, MA, United States
| | | | - Alexandra Werner
- Department of Immunology, Tufts University School of Medicine, Boston, MA, United States
- Immunology Graduate Program, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, United States
- C.S Mott Center for Human Growth and Development, Department of Obstetrics & Gynecology, Wayne State University School of Medicine, Detroit, MI, United States
| | - Anna Borchers
- Department of Immunology, Tufts University School of Medicine, Boston, MA, United States
| | - Vidya Iyer
- Department of Gynecology and Obstetrics, Tufts Medical Center, Boston, MA, United States
- Mass General Research Institute (MGRI), Division of Clinical Research, Massachusetts General Hospital, Boston, MA, United States
| | - Alison Vogell
- Department of Gynecology and Obstetrics, Tufts Medical Center, Boston, MA, United States
| | - Jared M. Fortier
- C.S Mott Center for Human Growth and Development, Department of Obstetrics & Gynecology, Wayne State University School of Medicine, Detroit, MI, United States
| | - Charles R. Wira
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States
| | - Marta Rodriguez-Garcia
- Department of Immunology, Tufts University School of Medicine, Boston, MA, United States
- Immunology Graduate Program, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, United States
- C.S Mott Center for Human Growth and Development, Department of Obstetrics & Gynecology, Wayne State University School of Medicine, Detroit, MI, United States
- Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, MI, United States
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Snyder JD, Yoon TW, Lee S, Halder P, Fitzpatrick EA, Yi AK. Protein kinase D1 in myeloid lineage cells contributes to the accumulation of CXCR3 +CCR6 + nonconventional Th1 cells in the lungs and potentiates hypersensitivity pneumonitis caused by S. rectivirgula. Front Immunol 2024; 15:1403155. [PMID: 39464896 PMCID: PMC11502317 DOI: 10.3389/fimmu.2024.1403155] [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: 03/18/2024] [Accepted: 09/18/2024] [Indexed: 10/29/2024] Open
Abstract
Introduction Hypersensitivity pneumonitis (HP) is an extrinsic allergic alveolitis characterized by inflammation of the interstitium, bronchioles, and alveoli of the lung that leads to granuloma formation. We previously found that activation of protein kinase D1 (PKD1) in the lungs following exposures to Saccharopolyspora rectivirgula contributes to the acute pulmonary inflammation, IL-17A expression in the lungs, and development of HP. In the present study, we investigated whether PKD1 in myeloid-lineage cells affects the pathogenic course of the S. rectivirgula-induced HP. Methods Mice were exposed intranasally to S. rectivirgula once or 3 times/week for 3 weeks. The protein and mRNA expression levels of cytokines/chemokines were detected by enzyme-linked immunosorbent assay and quantitative real-time PCR, respectively. Flow cytometry was used to detect the different types of immune cells and the levels of surface proteins. Lung tissue sections were stained with hematoxylin and eosin, digital images were captured, and immune cells influx into the interstitial lung tissue were detected. Results Compared to control PKD1-sufficient mice, mice with PKD1 deficiency in myeloid-lineage cells (PKD1mKO) showed significantly suppressed expression of TNFα, IFNγ, IL-6, CCL2, CCL3, CCL4, CXCL1, CXCL2, and CXCL10 and neutrophilic alveolitis after single intranasal exposure to S. rectivirgula. Substantially reduced levels of alveolitis and granuloma formation were observed in the PKD1mKO mice repeatedly exposed to S. rectivirgula for 3 weeks. In addition, expression levels of the Th1/Th17 polarizing cytokines and chemokines such as IFNγ, IL-17A, CXCL9, CXCL10, CXCL11, and CCL20 in lungs were significantly reduced in the PKD1mKO mice repeatedly exposed to S. rectivirgula. Moreover, accumulation of CXCR3+CCR6+ nonconventional Th1 in the lungs were significantly reduced in PKD1mKO mice repeatedly exposed to S. rectivirgula. Discussion Our results demonstrate that PKD1 in myeloid-lineage cells plays an essential role in the development and progress of HP caused by repeated exposure to S. rectivirgula by contributing Th1/Th17 polarizing proinflammatory responses, alveolitis, and accumulation of pathogenic nonconventional Th1 cells in the lungs.
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Affiliation(s)
- John D. Snyder
- Integrated Biomedical Science Graduate Program, The University of Tennessee Health Science Center, Memphis, TN, United States
- Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Tae Won Yoon
- Integrated Biomedical Science Graduate Program, The University of Tennessee Health Science Center, Memphis, TN, United States
- Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Sangmin Lee
- Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Priyanka Halder
- Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Elizabeth Ann Fitzpatrick
- Integrated Biomedical Science Graduate Program, The University of Tennessee Health Science Center, Memphis, TN, United States
- Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Ae-Kyung Yi
- Integrated Biomedical Science Graduate Program, The University of Tennessee Health Science Center, Memphis, TN, United States
- Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN, United States
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4
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Boll EJ, Lopez DV, Terne M, Hessing S, Parschat K, Jensen SR. Human milk oligosaccharides differentially support gut barrier integrity and enhance Th1 and Th17 cell effector responses in vitro. Front Immunol 2024; 15:1359499. [PMID: 38510254 PMCID: PMC10950922 DOI: 10.3389/fimmu.2024.1359499] [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: 12/21/2023] [Accepted: 02/15/2024] [Indexed: 03/22/2024] Open
Abstract
Human milk oligosaccharides (HMOs) can modulate the intestinal barrier and regulate immune cells to favor the maturation of the infant intestinal tract and immune system, but the precise functions of individual HMOs are unclear. To determine the structure-dependent effects of individual HMOs (representing different structural classes) on the intestinal epithelium as well as innate and adaptive immune cells, we assessed fucosylated (2'FL and 3FL), sialylated (3'SL and 6'SL) and neutral non-fucosylated (LNT and LNT2) HMOs for their ability to support intestinal barrier integrity, to stimulate the secretion of chemokines from intestinal epithelial cells, and to modulate cytokine release from LPS-activated dendritic cells (DCs), M1 macrophages (MØs), and co-cultures with naïve CD4+ T cells. The fucosylated and neutral non-fucosylated HMOs increased barrier integrity and protected the barrier following an inflammatory insult but exerted minimal immunomodulatory activity. The sialylated HMOs enhanced the secretion of CXCL10, CCL20 and CXCL8 from intestinal epithelial cells, promoted the secretion of several cytokines (including IL-10, IL-12p70 and IL-23) from LPS-activated DCs and M1 MØs, and increased the secretion of IFN-γ and IL-17A from CD4+ T cells primed by LPS-activated DCs and MØs while reducing the secretion of IL-13. Thus, 3'SL and 6'SL supported Th1 and Th17 responses while reducing Th2 responses. Collectively, our data show that HMOs exert structure-dependent effects on the intestinal epithelium and possess immunomodulatory properties that confer benefits to infants and possibly also later in life.
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Affiliation(s)
| | | | - Mandy Terne
- Chr. Hansen A/S, Applied HMOs, Hoersholm, Denmark
| | - Sara Hessing
- Chr. Hansen A/S, Applied HMOs, Hoersholm, Denmark
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Pampalone M, Cuscino N, Iannolo G, Amico G, Ricordi C, Vitale G, Carcione C, Castelbuono S, Scilabra SD, Coronnello C, Gruttadauria S, Pietrosi G. Human Amniotic MSC Response in LPS-Stimulated Ascites from Patients with Cirrhosis: FOXO1 Gene and Th17 Activation in Enhanced Antibacterial Activation. Int J Mol Sci 2024; 25:2801. [PMID: 38474048 DOI: 10.3390/ijms25052801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/22/2024] [Accepted: 02/23/2024] [Indexed: 03/14/2024] Open
Abstract
Spontaneous bacterial peritonitis (SBP) is a severe complication in patients with decompensated liver cirrhosis and is commonly treated with broad spectrum antibiotics. However, the rise of antibiotic resistance requires alternative therapeutic strategies. As recently shown, human amnion-derived mesenchymal stem cells (hA-MSCs) are able, in vitro, to promote bacterial clearance and modulate the immune and inflammatory response in SBP. Our results highlight the upregulation of FOXO1, CXCL5, CXCL6, CCL20, and MAPK13 in hA-MSCs as well as the promotion of bacterial clearance, prompting a shift in the immune response toward a Th17 lymphocyte phenotype after 72 h treatment. In this study, we used an in vitro SBP model and employed omics techniques (next-generation sequencing) to investigate the mechanisms by which hA-MSCs modify the crosstalk between immune cells in LPS-stimulated ascitic fluid. We also validated the data obtained via qRT-PCR, cytofluorimetric analysis, and Luminex assay. These findings provide further support to the hope of using hA-MSCs for the prevention and treatment of infective diseases, such as SBP, offering a viable alternative to antibiotic therapy.
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Affiliation(s)
- Mariangela Pampalone
- Ri.MED Foundation, 90127 Palermo, Italy
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | - Nicola Cuscino
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | - Gioacchin Iannolo
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | - Giandomenico Amico
- Ri.MED Foundation, 90127 Palermo, Italy
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | - Camillo Ricordi
- Cell Transplant Center, Diabetes Research Institute (DRI), University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL 33136, USA
| | | | | | - Salvatore Castelbuono
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | - Simone Dario Scilabra
- Ri.MED Foundation, 90127 Palermo, Italy
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | | | - Salvatore Gruttadauria
- Department for the Treatment and Study of Abdominal Disease and Abdominal Transplantation, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), UPMCI (University of Pittsburgh Medical Center Italy), 90127 Palermo, Italy
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, 95124 Catania, Italy
| | - Giada Pietrosi
- Department for the Treatment and Study of Abdominal Disease and Abdominal Transplantation, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), UPMCI (University of Pittsburgh Medical Center Italy), 90127 Palermo, Italy
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6
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Kubick N, Lazarczyk M, Strzałkowska N, Charuta A, Horbańczuk JO, Sacharczuk M, Mickael ME. Factors regulating the differences in frequency of infiltration of Th17 and Treg of the blood-brain barrier. Immunogenetics 2023; 75:417-423. [PMID: 37430007 DOI: 10.1007/s00251-023-01310-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 05/23/2023] [Indexed: 07/12/2023]
Abstract
Controlling CD4+ immune cell infiltration of the brain is a leading aim in designing therapeutic strategies for a range of neuropathological disorders such as multiple sclerosis, Alzheimer's disease, and depression. CD4+ T cells are a highly heterogeneous and reprogrammable family, which includes various distinctive cell types such as Th17, Th1, and Treg cells. Interestingly Th17 and Treg cells share a related transcriptomic profile, where the TGFβ-SMADS pathway plays a fundamental role in regulating the differentiation of both of these cell types. However, Th17 could be highly pathogenic and was shown to promote inflammation in various neuropathological disorders. Conversely, Treg is anti-inflammatory and is known to inhibit Th17. It could be noticed that Th17 frequencies of infiltration of the blood-brain barrier in various neurological disorders are significantly upregulated. However, Treg infiltration numbers are significantly low. The reasons behind these contradicting observations are still unknown. In this perspective, we propose that the difference in the T-cell receptor repertoire diversity, diapedesis pathways, chemokine expression, and mechanical properties of these two cell types could be contributing to answering this intriguing question.
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Affiliation(s)
- Norwin Kubick
- Department of Biology, Institute of Plant Science and Microbiology, University of Hamburg, Ohnhorststr. 18, 22609, Hamburg, Germany
| | - Marzena Lazarczyk
- Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Ul. Postepu 36A, Jastrzębiec, 05-552, Magdalenka, Poland
| | - Nina Strzałkowska
- Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Ul. Postepu 36A, Jastrzębiec, 05-552, Magdalenka, Poland
| | - Anna Charuta
- Institute of Health, Siedlce University of Natural Sciences and Humanities, Ul. Konarskiego 2, 08-110, Siedlce, Poland
| | - Jarosław Olav Horbańczuk
- Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Ul. Postepu 36A, Jastrzębiec, 05-552, Magdalenka, Poland
| | - Mariusz Sacharczuk
- Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Ul. Postepu 36A, Jastrzębiec, 05-552, Magdalenka, Poland.
- Department of Pharmacodynamics, Faculty of Pharmacy, Warsaw Medical University, L Banacha 1, 02-697, Warsaw, Poland.
| | - Michel Edwar Mickael
- Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Ul. Postepu 36A, Jastrzębiec, 05-552, Magdalenka, Poland.
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7
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Nguyen LTH, Ahn SH, Shin HM, Yang IJ. Anti-Psoriatic Effect of Rheum palmatum L. and Its Underlying Molecular Mechanisms. Int J Mol Sci 2022; 23:16000. [PMID: 36555642 PMCID: PMC9781959 DOI: 10.3390/ijms232416000] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/14/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Psoriasis is a chronic, immune-mediated inflammatory skin disorder. Rheum palmatum L. is a common traditional medicinal herb with anti-inflammatory and immunomodulatory activities. This study aimed to investigate the anti-psoriatic effects of the ethanolic extract from R. palmatum L. (RPE) and its chemical constituents, as well as the mechanisms underlying their therapeutic significance. An imiquimod (IMQ)-induced psoriasis-like mouse model was used to examine the anti-psoriatic effect of RPE in vivo. Network pharmacological analysis was performed to investigate the potential targets and related pathways of the RPE components, including rhein, emodin, chrysophanol, aloe-emodin, and physcion. The anti-inflammatory effects and underlying mechanisms of these components were examined using in vitro models. Topical application of RPE alleviated psoriasis-like symptoms and reduced levels of inflammatory cytokines and proliferation markers in the skin. Network pharmacological analysis revealed that RPE components target 20 genes that are linked to psoriasis-related pathways, such as IL-17, MAPK, and TNF signaling pathways. Among the five components of RPE, rhein and emodin showed inhibitory effects on TNF-α and IL-17 production in EL-4 cells, attenuated the production of CXCL8, CXCL10, CCL20, and MMP9, and reduced proliferation in HaCaT cells. Chrysophanol, aloe-emodin, and physcion were less effective than rhein and emodin in suppressing inflammatory responses and keratinocyte proliferation. The effects of these compounds might occur through the inhibition of the ERK, STAT3, and NF-κB signaling pathways. This study suggested the anti-psoriatic effect of RPE, with rhein and emodin as the main contributors that regulate multiple signaling pathways.
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Affiliation(s)
- Ly Thi Huong Nguyen
- Department of Physiology, College of Korean Medicine, Dongguk University, Gyeongju 38066, Republic of Korea
| | - Sang-Hyun Ahn
- Department of Anatomy, College of Korean Medicine, Semyung University, Jecheon-si 27136, Republic of Korea
| | - Heung-Mook Shin
- Department of Physiology, College of Korean Medicine, Dongguk University, Gyeongju 38066, Republic of Korea
| | - In-Jun Yang
- Department of Physiology, College of Korean Medicine, Dongguk University, Gyeongju 38066, Republic of Korea
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8
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Wang X, Yip KC, He A, Tang J, Liu S, Yan R, Zhang Q, Li R. Plasma Olink Proteomics Identifies CCL20 as a Novel Predictive and Diagnostic Inflammatory Marker for Preeclampsia. J Proteome Res 2022; 21:2998-3006. [PMID: 36301636 PMCID: PMC9724708 DOI: 10.1021/acs.jproteome.2c00544] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Indexed: 01/19/2023]
Abstract
Inflammation is generally thought to be involved in the occurrence and development of preeclampsia (PE), but its specific effect on PE remains unclear. In the present study, the expression levels of 92 inflammation-related proteins were measured in the late pregnancy maternal plasma from patients with PE (n = 15) and normal pregnant controls (n = 15) using the Olink inflammation panel based on the highly sensitive and specific proximity extension assay technology. A total of 28 inflammation-related markers differed between the PE and control groups. Among them, fibroblast growth factor 21 (FGF-21) and cysteine-cysteine motif chemokine ligand 20 (CCL20) had the largest fold changes. We further validated the levels of CCL20 in the late (43 with PE and 44 controls) and early (37 with PE and 37 controls) pregnancy maternal plasma using enzyme-linked immunosorbent assay (ELISA). To the best of our knowledge, for the first time, CCL20 was found to be upregulated in the late and early pregnancy plasma of patients with PE and had an area under the curve (AUC) of 0.753 and 0.668, respectively. In conclusion, patients with PE had increased levels of most inflammatory markers, and CCL20 might be a novel potential predictive and diagnostic biomarker for PE.
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Affiliation(s)
- Xiufang Wang
- Department
of Obstetrics and Gynecology, The First
Affiliated Hospital of Jinan University, No. 613, Huangpu Road West, Tianhe
District, Guangzhou 510630, Guangdong, China
| | - Ka Cheuk Yip
- Department
of Obstetrics and Gynecology, The First
Affiliated Hospital of Jinan University, No. 613, Huangpu Road West, Tianhe
District, Guangzhou 510630, Guangdong, China
| | - Andong He
- Department
of Obstetrics and Gynecology, The First
Affiliated Hospital of Jinan University, No. 613, Huangpu Road West, Tianhe
District, Guangzhou 510630, Guangdong, China
| | - Jinqing Tang
- Department
of Obstetrics and Gynecology, Qingyuan People’s
Hospital, Qingyuan 511518, Guangdong, China
| | - Shisan Liu
- Department
of Obstetrics and Gynecology, The First
Affiliated Hospital of Jinan University, No. 613, Huangpu Road West, Tianhe
District, Guangzhou 510630, Guangdong, China
| | - Ruiling Yan
- Department
of Fetal Medicine, The First Affiliated
Hospital of Jinan University, Guangzhou 510630, Guangdong, China
| | - Qiao Zhang
- Institute
of Molecular and Medical Virology, School of Medicine, Jinan University, No. 601, Huangpu Road West, Tianhe
District, Guangzhou 510632, Guangdong, China
| | - Ruiman Li
- Department
of Obstetrics and Gynecology, The First
Affiliated Hospital of Jinan University, No. 613, Huangpu Road West, Tianhe
District, Guangzhou 510630, Guangdong, China
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Ortega MA, Gómez-Lahoz AM, Sánchez-Trujillo L, Fraile-Martinez O, García-Montero C, Guijarro LG, Bravo C, De Leon-Luis JA, Saz JV, Bujan J, García-Honduvilla N, Monserrat J, Alvarez-Mon M. Chronic Venous Disease during Pregnancy Causes a Systematic Increase in Maternal and Fetal Proinflammatory Markers. Int J Mol Sci 2022; 23:ijms23168976. [PMID: 36012236 PMCID: PMC9409364 DOI: 10.3390/ijms23168976] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/09/2022] [Accepted: 08/10/2022] [Indexed: 11/16/2022] Open
Abstract
Chronic venous disease (CVD) is a common vascular disorder characterized by increased venous hypertension and insufficient venous return from the lower limbs. Pregnancy is a high-risk situation for developing CVD. Approximately a third of the women will develop this condition during pregnancy, and similarly to arterial hypertensive disorders, previous evidence has described a plethora of alterations in placental structure and function in women with pregnancy-induced CVD. It is widely known that arterial-induced placenta dysfunction is accompanied by an important immune system alteration along with increased inflammatory markers, which may provide detrimental consequences for the women and their offspring. However, to our knowledge, there are still no data collected regarding cytokine profiling in women with pregnancy-induced CVD. Thus, the aim of the present work was to examine cytokine signatures in the serum of pregnant women (PW) with CVD and their newborns (NB). This study was conducted through a multiplex technique in 62 PW with pregnancy-induced CVD in comparison to 52 PW without CVD (HC) as well as their NB. Our results show significant alterations in a broad spectrum of inflammatory cytokines (IL-6, IL-12, TNF-α, IL-10, IL-13, IL-2, IL-7, IFN-γ, IL-4, IL-5, IL-21, IL-23, GM-CSF, chemokines (fractalkine), MIP-3α, and MIP-1β). Overall, we demonstrate that pregnancy-induced CVD is associated with a proinflammatory environment, therefore highlighting the potentially alarming consequences of this condition for maternal and fetal wellbeing.
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Affiliation(s)
- Miguel A. Ortega
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Correspondence:
| | - Ana M. Gómez-Lahoz
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Lara Sánchez-Trujillo
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain
- Service of Pediatric, Hospital Universitario Principe de Asturias, 28801 Alcalá de Henares, Spain
| | - Oscar Fraile-Martinez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain
| | - Cielo García-Montero
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain
| | - Luis G. Guijarro
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Department of Systems Biology, Faculty of Medicine and Health Sciences (Networking Research Center on for Liver and Digestive Diseases (CIBEREHD)), University of Alcalá, 28801 Alcalá de Henares, Spain
| | - Coral Bravo
- Department of Public and Maternal and Child Health, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Department of Obstetrics and Gynecology, University Hospital Gregorio Marañón, 28009 Madrid, Spain
- Health Research Institute Gregorio Marañón, 28009 Madrid, Spain
| | - Juan A. De Leon-Luis
- Department of Public and Maternal and Child Health, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Department of Obstetrics and Gynecology, University Hospital Gregorio Marañón, 28009 Madrid, Spain
- Health Research Institute Gregorio Marañón, 28009 Madrid, Spain
| | - Jose V. Saz
- Health Research Institute Gregorio Marañón, 28009 Madrid, Spain
| | - Julia Bujan
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Natalio García-Honduvilla
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Jorge Monserrat
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Melchor Alvarez-Mon
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Department of Biomedicine and Biotechnology, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain
- Immune System Diseases-Rheumatology and Internal Medicine Service, University Hospital Príncipe de Asturias, CIBEREHD, 28806 Alcalá de Henares, Spain
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10
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Melin A, Routier É, Roy S, Pradere P, Le Pavec J, Pierre T, Chanson N, Scoazec JY, Lambotte O, Robert C. Sarcoid-like Granulomatosis Associated with Immune Checkpoint Inhibitors in Melanoma. Cancers (Basel) 2022; 14:cancers14122937. [PMID: 35740604 PMCID: PMC9221061 DOI: 10.3390/cancers14122937] [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: 05/09/2022] [Revised: 06/03/2022] [Accepted: 06/07/2022] [Indexed: 02/05/2023] Open
Abstract
We aimed to review the clinical and biological presentation of granulomatosis associated with immune-checkpoint inhibitors (ICI) in patients with melanoma and to explore its association with classical sarcoidosis as well as with cancer response to ICI. To this end, a retrospective study on 18 melanoma patients with histologically proven ICI-induced granulomatosis over a 12-year period in a single center, as well as on 67 similar cases reported in the literature, was conducted. Results indicate ICI-induced granulomatosis is an early side effect (median time to onset: 2 months). Its clinical presentation, with predominant (90%) thoracic involvement, histopathological appearance and supposed underlying biology (involving the mTOR pathway in immune cells, Th17 polarization and TReg dysfunction) are indistinguishable from those of sarcoidosis. Moreover, it appears to be associated with ICI benefit (>65% objective response rate). Evolution is generally favorable, and symptomatic steroid treatment and/or ICI discontinuation are rarely necessary. ICI-associated granulomatosis is critical to explore for several reasons. Practically, it is essential to differentiate it from cancer progression. Secondly, this “experimental” sarcoidosis brings new elements that may help to address sarcoidosis origin and pathophysiology. Its association with ICI efficacy must be confirmed on a larger scale but could have significant impacts on patient management and biomarker definition.
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Affiliation(s)
- Audrey Melin
- Department of Dermatology, Gustave Roussy, 114 rue Edouard-Vaillant, 94800 Villejuif, France; (É.R.); (S.R.)
- Correspondence: (A.M.); (C.R.)
| | - Émilie Routier
- Department of Dermatology, Gustave Roussy, 114 rue Edouard-Vaillant, 94800 Villejuif, France; (É.R.); (S.R.)
| | - Séverine Roy
- Department of Dermatology, Gustave Roussy, 114 rue Edouard-Vaillant, 94800 Villejuif, France; (É.R.); (S.R.)
| | - Pauline Pradere
- Service de Pneumologie et Transplantation Pulmonaire, Hôpital Marie-Lannelongue, Groupe Hospitalier Paris-Saint Joseph, 133 Av. de la Résistance, 92350 Le Plessis-Robinson, France; (P.P.); (J.L.P.)
| | - Jerome Le Pavec
- Service de Pneumologie et Transplantation Pulmonaire, Hôpital Marie-Lannelongue, Groupe Hospitalier Paris-Saint Joseph, 133 Av. de la Résistance, 92350 Le Plessis-Robinson, France; (P.P.); (J.L.P.)
| | - Thibaut Pierre
- Department of Medical Imaging, Gustave Roussy, 114 rue Edouard-Vaillant, 94800 Villejuif, France;
| | - Noémie Chanson
- Department of Internal Medicine, Kremlin Bicêtre Hospital, 78 rue du Général Leclerc, 94270 Le Kremlin Bicêtre, France; (N.C.); (O.L.)
| | - Jean-Yves Scoazec
- Université Paris Saclay, AP-HP, 63 rue Gabriel Péri, 94270 Le Kremlin Bicêtre, France;
- Department of Pathology, Gustave Roussy, 114 rue Edouard-Vaillant, 94800 Villejuif, France
| | - Olivier Lambotte
- Department of Internal Medicine, Kremlin Bicêtre Hospital, 78 rue du Général Leclerc, 94270 Le Kremlin Bicêtre, France; (N.C.); (O.L.)
- Université Paris Saclay, AP-HP, 63 rue Gabriel Péri, 94270 Le Kremlin Bicêtre, France;
| | - Caroline Robert
- Department of Dermatology, Gustave Roussy, 114 rue Edouard-Vaillant, 94800 Villejuif, France; (É.R.); (S.R.)
- Université Paris Saclay, AP-HP, 63 rue Gabriel Péri, 94270 Le Kremlin Bicêtre, France;
- Correspondence: (A.M.); (C.R.)
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11
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Plasminogen and plasmin can bind to human T cells and generate truncated CCL21 that increases dendritic cell chemotactic responses. J Biol Chem 2022; 298:102112. [PMID: 35690148 PMCID: PMC9270246 DOI: 10.1016/j.jbc.2022.102112] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 06/02/2022] [Accepted: 06/03/2022] [Indexed: 11/22/2022] Open
Abstract
Plasmin is a broad-spectrum protease and therefore needs to be tightly regulated. Active plasmin is formed from plasminogen, which is found in high concentrations in the blood and is converted by the plasminogen activators. In the circulation, high levels of α2-antiplasmin rapidly and efficiently inhibit plasmin activity. Certain myeloid immune cells have been shown to bind plasmin and plasminogen on their cell surface via proteins that bind to the plasmin(ogen) kringle domains. Our earlier work showed that T cells can activate plasmin, but that they do not themselves express plasminogen. Here, we demonstrate that T cells express several known plasminogen receptors, and that they bind plasminogen on their cell surface. We show T cell-bound plasminogen was converted to plasmin by plasminogen activators upon T cell activation. To examine functional consequences of plasmin generation by activated T cells, we investigated its effect on the chemokine, C-C Motif Chemokine Ligand 21 (CCL21). Video microscopy and western blotting confirmed that plasmin bound by human T cells cleaves CCL21 and increases the chemotactic response of monocyte-derived dendritic cells towards higher CCL21 concentrations along the concentration gradient by increasing their directional migration and track straightness. These results demonstrate how migrating T cells and potentially other activated immune cells may co-opt a powerful proteolytic system from the plasma towards immune processes in the peripheral tissues, where α2-antiplasmin is more likely to be absent. We propose that plasminogen bound to migrating immune cells may strongly modulate chemokine responses in peripheral tissues.
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12
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Gideon HP, Hughes TK, Tzouanas CN, Wadsworth MH, Tu AA, Gierahn TM, Peters JM, Hopkins FF, Wei JR, Kummerlowe C, Grant NL, Nargan K, Phuah JY, Borish HJ, Maiello P, White AG, Winchell CG, Nyquist SK, Ganchua SKC, Myers A, Patel KV, Ameel CL, Cochran CT, Ibrahim S, Tomko JA, Frye LJ, Rosenberg JM, Shih A, Chao M, Klein E, Scanga CA, Ordovas-Montanes J, Berger B, Mattila JT, Madansein R, Love JC, Lin PL, Leslie A, Behar SM, Bryson B, Flynn JL, Fortune SM, Shalek AK. Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control. Immunity 2022; 55:827-846.e10. [PMID: 35483355 PMCID: PMC9122264 DOI: 10.1016/j.immuni.2022.04.004] [Citation(s) in RCA: 129] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 02/08/2022] [Accepted: 04/07/2022] [Indexed: 12/12/2022]
Abstract
Mycobacterium tuberculosis lung infection results in a complex multicellular structure: the granuloma. In some granulomas, immune activity promotes bacterial clearance, but in others, bacteria persist and grow. We identified correlates of bacterial control in cynomolgus macaque lung granulomas by co-registering longitudinal positron emission tomography and computed tomography imaging, single-cell RNA sequencing, and measures of bacterial clearance. Bacterial persistence occurred in granulomas enriched for mast, endothelial, fibroblast, and plasma cells, signaling amongst themselves via type 2 immunity and wound-healing pathways. Granulomas that drove bacterial control were characterized by cellular ecosystems enriched for type 1-type 17, stem-like, and cytotoxic T cells engaged in pro-inflammatory signaling networks involving diverse cell populations. Granulomas that arose later in infection displayed functional characteristics of restrictive granulomas and were more capable of killing Mtb. Our results define the complex multicellular ecosystems underlying (lack of) granuloma resolution and highlight host immune targets that can be leveraged to develop new vaccine and therapeutic strategies for TB.
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Affiliation(s)
- Hannah P Gideon
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA
| | - Travis K Hughes
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Constantine N Tzouanas
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Marc H Wadsworth
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Ang Andy Tu
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Todd M Gierahn
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Joshua M Peters
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Forrest F Hopkins
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Jun-Rong Wei
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Conner Kummerlowe
- Program in Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Nicole L Grant
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | | | - Jia Yao Phuah
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - H Jacob Borish
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Pauline Maiello
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Alexander G White
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Caylin G Winchell
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA; Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Sarah K Nyquist
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Sharie Keanne C Ganchua
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Amy Myers
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Kush V Patel
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Cassaundra L Ameel
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Catherine T Cochran
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Samira Ibrahim
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Jaime A Tomko
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Lonnie James Frye
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jacob M Rosenberg
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA
| | - Angela Shih
- Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA
| | - Michael Chao
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Edwin Klein
- Division of Laboratory Animal Research, University of Pittsburgh, Pittsburgh PA, USA
| | - Charles A Scanga
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jose Ordovas-Montanes
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Bonnie Berger
- Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Joshua T Mattila
- Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA; Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Rajhmun Madansein
- Department of Cardiothoracic Surgery, University of KwaZulu Natal, Durban, South Africa
| | - J Christopher Love
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Philana Ling Lin
- Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pediatrics, University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Alasdair Leslie
- Africa Health Research Institute, Durban, South Africa; School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa; Department of Infection and Immunity, University College London, London, UK
| | - Samuel M Behar
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA
| | - Bryan Bryson
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - JoAnne L Flynn
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Sarah M Fortune
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Alex K Shalek
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA; The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
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13
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Hu L, Zhao X, Li P, Zeng Y, Zhang Y, Shen Y, Wang Y, Sun X, Lai B, Zhong C. Proximal and Distal Regions of Pathogenic Th17 Related Chromatin Loci Are Sequentially Accessible During Pathogenicity of Th17. Front Immunol 2022; 13:864314. [PMID: 35514969 PMCID: PMC9062102 DOI: 10.3389/fimmu.2022.864314] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/17/2022] [Indexed: 11/13/2022] Open
Abstract
Pathogenic Th17, featured by their production of pro-inflammatory cytokines, are considered as a key player in most autoimmune diseases. The transcriptome of them is obviously distinct from that of conventional regulatory Th17. However, chromatin accessibility of the two Th17 groups have not been comprehensively compared yet. Here, we found that their chromatin-accessible regions(ChARs) significantly correlated with the expression of related genes, indicating that they might engage in the regulation of these genes. Indeed, pathogenic Th17 specific ChARs (patho-ChARs) exhibited a significant distribution preference in TSS-proximal region. We further filtered the patho-ChARs based on their conservation among mammalians or their concordance with the expression of their related genes. In either situation, the filtered patho-ChARs also showed a preference for TSS-proximal region. Enrichment of expression concordant patho-ChARs related genes suggested that they might involve in the pathogenicity of Th17. Thus, we also examined all ChARs of patho-ChARs related genes, and defined an opening ChAR set according to their changes in the Th17 to Th1 conversion. Interestingly, these opening ChARs displayed a sequential accessibility change from TSS-proximal region to TSS-distal region. Meanwhile, a group of patho-TFs (transcription factors) were identified based on the appearance of their binding motifs in the opening ChARs. Consistently, some of them also displayed a similar preference for binding the TSS-proximal region. Single-cell transcriptome analysis further confirmed that these patho-TFs were involved in the generation of pathogenic Th17. Therefore, our results shed light on a new regulatory mechanism underlying the generation of pathogenic Th17, which is worth to be considered for autoimmune disease therapy.
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Affiliation(s)
- Luni Hu
- Beijing Key Laboratory of Tumor Systems Biology, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xingyu Zhao
- Beijing Key Laboratory of Tumor Systems Biology, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Peng Li
- Beijing Key Laboratory of Tumor Systems Biology, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yanyu Zeng
- Beijing Key Laboratory of Tumor Systems Biology, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yime Zhang
- Beijing Key Laboratory of Tumor Systems Biology, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yang Shen
- School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yukai Wang
- School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xiaolin Sun
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.,Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing, China
| | - Binbin Lai
- Biomedical Engineering Department, Peking University, Beijing, China.,Institute of Medical Technology, Peking University Health Science Center, Beijing, China.,Department of Dermatology and Venereology, Peking University First Hospital, Beijing, China
| | - Chao Zhong
- Beijing Key Laboratory of Tumor Systems Biology, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.,National Health Commission (NHC) Key Laboratory of Medical Immunology, Peking University, Beijing, China.,Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing, China
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14
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Nguyen LTH, Choi MJ, Shin HM, Yang IJ. Coptisine Alleviates Imiquimod-Induced Psoriasis-like Skin Lesions and Anxiety-like Behavior in Mice. Molecules 2022; 27:1412. [PMID: 35209199 PMCID: PMC8878104 DOI: 10.3390/molecules27041412] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/16/2022] [Accepted: 02/16/2022] [Indexed: 02/04/2023] Open
Abstract
Psoriasis is a common inflammatory skin disorder, which can be associated with psychological disorders, such as anxiety and depression. This study investigated the efficacy and the mechanism of action of a natural compound coptisine using imiquimod (IMQ)-induced psoriasis mice. Coptisine reduced the severity of psoriasis-like skin lesions, decreased epidermal hyperplasia and the levels of inflammatory cytokines TNF-α, IL-17, and IL-22. Furthermore, coptisine improved IMQ-induced anxiety in mice by increasing the number of entries and time in open arms in the elevated plus maze (EPM) test. Coptisine also lowered the levels of inflammatory cytokines TNF-α and IL-1β in the prefrontal cortex of psoriasis mice. HaCaT keratinocytes and BV2 microglial cells were used to investigate the effects of coptisine in vitro. In M5-treated HaCaT cells, coptisine decreased the production of IL-6, MIP-3α/CCL20, IP-10/CXCL10, and ICAM-1 and suppressed the NF-κB signaling pathway. In LPS-stimulated BV2 cells, coptisine reduced the secretion of TNF-α and IL-1β. These findings suggest that coptisine might be a potential candidate for psoriasis treatment by improving both disease severity and psychological comorbidities.
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Affiliation(s)
| | | | - Heung-Mook Shin
- Department of Physiology, College of Korean Medicine, Dongguk University, Gyeongju 38066, Korea; (L.T.H.N.); (M.-J.C.)
| | - In-Jun Yang
- Department of Physiology, College of Korean Medicine, Dongguk University, Gyeongju 38066, Korea; (L.T.H.N.); (M.-J.C.)
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15
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Gibson BHY, Wollenman CC, Moore-Lotridge SN, Keller PR, Summitt JB, Revenko AR, Flick MJ, Blackwell TS, Schoenecker JG. Plasmin drives burn-induced systemic inflammatory response syndrome. JCI Insight 2021; 6:154439. [PMID: 34877937 PMCID: PMC8675186 DOI: 10.1172/jci.insight.154439] [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: 08/27/2021] [Accepted: 10/27/2021] [Indexed: 12/12/2022] Open
Abstract
Severe injuries, such as burns, provoke a systemic inflammatory response syndrome (SIRS) that imposes pathology on all organs. Simultaneously, severe injury also elicits activation of the fibrinolytic protease plasmin. While the principal adverse outcome of plasmin activation in severe injury is compromised hemostasis, plasmin also possesses proinflammatory properties. We hypothesized that, following a severe injury, early activation of plasmin drives SIRS. Plasmin activation was measured and related to injury severity, SIRS, coagulopathy, and outcomes prospectively in burn patients who are not at risk of hemorrhage. Patients exhibited early, significant activation of plasmin that correlated with burn severity, cytokines, coagulopathy, and death. Burn with a concomitant, remote muscle injury was employed in mice to determine the role of plasmin in the cytokine storm and inflammatory cascades in injured tissue distant from the burn injury. Genetic and pharmacologic inhibition of plasmin reduced the burn-induced cytokine storm and inflammatory signaling in injured tissue. These findings demonstrate (a) that severe injury-induced plasmin activation is a key pathologic component of the SIRS-driven cytokine storm and SIRS-activated inflammatory cascades in tissues distant from the inciting injury and (b) that targeted inhibition of plasmin activation may be effective for limiting both hemorrhage and tissue-damaging inflammation following injury.
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Affiliation(s)
| | - Colby C Wollenman
- School of Medicine.,Department of Orthopaedic Surgery, Vanderbilt University Medical Center
| | - Stephanie N Moore-Lotridge
- Department of Orthopaedic Surgery, Vanderbilt University Medical Center.,Vanderbilt Center for Bone Biology
| | | | - J Blair Summitt
- Department of Plastic Surgery, Vanderbilt University Medical Center; and.,Vanderbilt University Medical Center Burn Center, Vanderbilt University, Nashville, Tennessee, USA
| | - Alexey R Revenko
- IONIS Pharmaceuticals Pulmonary and Oncology Drug Discovery, Carlsbad, California, USA
| | - Matthew J Flick
- Department of Pathology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.,University of North Carolina Blood Research Center, Chapel Hill, North Carolina, USA
| | - Timothy S Blackwell
- Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.,Division of Pulmonary and Critical Care
| | - Jonathan G Schoenecker
- Department of Pharmacology.,Department of Orthopaedic Surgery, Vanderbilt University Medical Center.,Vanderbilt Center for Bone Biology.,Department of Pathology, Microbiology, and Immunology; and.,Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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16
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Seillier C, Hélie P, Petit G, Vivien D, Clemente D, Le Mauff B, Docagne F, Toutirais O. Roles of the tissue-type plasminogen activator in immune response. Cell Immunol 2021; 371:104451. [PMID: 34781155 PMCID: PMC8577548 DOI: 10.1016/j.cellimm.2021.104451] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 10/06/2021] [Accepted: 10/29/2021] [Indexed: 11/30/2022]
Abstract
The COVID-19 pandemic has once again
brought to the forefront the existence of a tight link between the
coagulation/fibrinolytic system and the immunologic processes.
Tissue-type plasminogen activator (tPA) is a serine protease with a key
role in fibrinolysis by converting plasminogen into plasmin that can
finally degrade fibrin clots. tPA is released in the blood by endothelial
cells and hepatocytes but is also produced by various types of immune
cells including T cells and monocytes. Beyond its role on hemostasis, tPA
is also a potent modulator of inflammation and is involved in the
regulation of several inflammatory diseases. Here, after a brief
description of tPA structure, we review its new functions in adaptive
immunity focusing on T cells and antigen presenting cells. We intend to
synthesize the recent knowledge on proteolysis- and receptor-mediated
effects of tPA on immune response in physiological and pathological
context.
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Affiliation(s)
- Célia Seillier
- Normandie Univ, UNICAEN, INSERM, GIP Cyceron, Institut Blood and Brain @Caen-Normandie (BB@C), UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Caen, France
| | - Pauline Hélie
- Normandie Univ, UNICAEN, INSERM, GIP Cyceron, Institut Blood and Brain @Caen-Normandie (BB@C), UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Caen, France
| | - Gautier Petit
- Normandie Univ, UNICAEN, INSERM, GIP Cyceron, Institut Blood and Brain @Caen-Normandie (BB@C), UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Caen, France; Department of Immunology and Histocompatibility (HLA), Caen University Hospital, CHU Caen, France
| | - Denis Vivien
- Normandie Univ, UNICAEN, INSERM, GIP Cyceron, Institut Blood and Brain @Caen-Normandie (BB@C), UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Caen, France; Department of Clinical Research, Caen University Hospital, CHU Caen, France
| | - Diego Clemente
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, Finca La Peraleda s/n, 45071 Toledo, Spain
| | - Brigitte Le Mauff
- Normandie Univ, UNICAEN, INSERM, GIP Cyceron, Institut Blood and Brain @Caen-Normandie (BB@C), UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Caen, France; Department of Immunology and Histocompatibility (HLA), Caen University Hospital, CHU Caen, France
| | - Fabian Docagne
- Normandie Univ, UNICAEN, INSERM, GIP Cyceron, Institut Blood and Brain @Caen-Normandie (BB@C), UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Caen, France
| | - Olivier Toutirais
- Normandie Univ, UNICAEN, INSERM, GIP Cyceron, Institut Blood and Brain @Caen-Normandie (BB@C), UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Caen, France; Department of Immunology and Histocompatibility (HLA), Caen University Hospital, CHU Caen, France.
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Zhou G, Kong WS, Li ZC, Xie RF, Yu TY, Zhou X. Effects of Qing Chang Suppository Powder and its Ingredients on IL-17 Signal Pathway in HT-29 Cells and DSS-induced Mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 87:153573. [PMID: 34052543 DOI: 10.1016/j.phymed.2021.153573] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/08/2021] [Accepted: 04/09/2021] [Indexed: 05/25/2023]
Abstract
BACKGROUND Qingchang Suppository, a formula used for more than 30 years in Longhua Hospital, has shown satisfactory clinical effects on Ulcerative Colitis (UC). However, its therapeutic mechanism has not been fully elucidated. PURPOSE The study aims to investigate the effects of Qingchang Suppository powder (QCSP) and its ingredients by regulating the IL-17A signaling pathway which plays an important role in the development of UC. METHODS HPLC was used to analyze the main ingredients (Gallic acid, Indigo, Indirubin) in QCSP. HT-29 cells were induced by rhIL-17A and TNF-α, and IL-17A related protein expressions were determined by western blot. BALB/C mice were induced by 4% Dextran Sodium sulfate (DSS). The effects of QCSP and its ingredients were evaluated by measuring weight loss, disease activity index (DAI), colon length, histological analysis. Western blot was used for analysis of IL-17A and MAPK related proteins p-ERK, p-JNK, p-P38. Quantitative reverse transcription polymerase chain reaction (q-PCR) was used to detect the expression of IL-17A, HSP90 and ACT1 in colon tissue. Cytokines such as IL-17A, IL-1β, IFN-γ and TNF-α were determinated by enzyme-linked immunosorbent assay (ELISA). RESULTS QCSP had good therapeutic effect on DSS-induced colitis in mice. QCSP significantly relieved weight loss, restored colon length, repaired colon lesions, reduced histological scores and DAI, decreased TNF-α, IL-1β, IL-17 and IFN-γ contents, significantly suppressed the gene expressions of IL-17A, ACT1 and HSP90, and up-regulated the expressions of tight junction proteins like ZO-1 and Occludin. IL-17A pathway related proteins such as IL-17A, IL-17RA, HSP90, MAPKs, P-iκbα and iNOS were significantly increased in vitro and in vivo. CONCLUSIONS This paper reveals that QCSP inhibited the IL-17A signaling pathway in HT-29 cells and DSS induced mice, presenting a new mechanism of QCS on treating UC.
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Affiliation(s)
- Gui Zhou
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Wei-Song Kong
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Zhi-Cheng Li
- Pudong Hospital, Fudan University, Shanghai, China
| | - Rui-Fang Xie
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | | | - Xin Zhou
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
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18
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Levraut M, Bourg V, Capet N, Delourme A, Honnorat J, Thomas P, Lebrun-Frenay C. Cerebrospinal Fluid IL-17A Could Predict Acute Disease Severity in Non-NMDA-Receptor Autoimmune Encephalitis. Front Immunol 2021; 12:673021. [PMID: 34054854 PMCID: PMC8158812 DOI: 10.3389/fimmu.2021.673021] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 04/27/2021] [Indexed: 12/17/2022] Open
Abstract
Introduction Most of our knowledge into autoimmune encephalitis (AE) comes from N-Methyl-D-Aspartate Receptor (NMDAR) encephalitis. The concentrations of cytokines in cerebrospinal fluid (CSF) including IL-17A have been found to be increased and associated with poor outcome. However, data on the cytokine concentration in CSF and its correlation with outcome is lacking for other types of AE. Objective To report the concentrations of CSF sIL-2R, IL-6, IL-8, IL-10 and IL-17A and to correlate it with acute disease severity and the 1-year outcome in non-NMDAR AE. Methods We measured the CSF concentration of each cytokine in 20 AE patients, and compared IL-6 and IL-17A concentrations with 13 patients with CNS demyelinating diseases and 20 non-inflammatory controls. Patients were > 18yr and had at least 1-year clinical follow-up. Intracellular and NMDAR antibody (Ab) -mediated encephalitis were excluded. A mRS ≤ 2 was retained as a 1-year good outcome. Results The IL-17A concentration in CSF was higher in AE patients than in both control groups (p<0.01). No difference was observed in CSF concentration of IL-6 between groups. At disease onset, a high CSF IL-17A concentration correlated with a high modified Rankin Scale (p<0.05), a high Clinical Assessment Scale for Autoimmune Encephalitis score (p<0.001) and ICU admission (p<0.01). There was no correlation between the concentration of all CSF cytokines and the 1-year clinical outcome. Conclusion Our results show that CSF IL-17A could be interesting to assess initial severity in non-NMDAR AE. Thus, CSF IL-17A could be an interesting therapeutic target and be useful to assess early selective immunosuppressive therapy.
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Affiliation(s)
- Michael Levraut
- URRIS, Unité de Recherche Clinique Cote d'Azur-UR2CA, CRCSEP, Hôpital Pasteur 2, Centre Hospitalier Universitaire de Nice, Nice, France.,Internal Medicine Department, Hôpital l'Archet 1, Centre Hospitalier Universitaire de Nice, Nice, France
| | - Véronique Bourg
- Neurology Department, Hôpital Pasteur 2, Centre Hospitalier Universitaire de Nice, Nice, France
| | - Nicolas Capet
- URRIS, Unité de Recherche Clinique Cote d'Azur-UR2CA, CRCSEP, Hôpital Pasteur 2, Centre Hospitalier Universitaire de Nice, Nice, France.,Neurology Department, Hôpital Pasteur 2, Centre Hospitalier Universitaire de Nice, Nice, France
| | - Adrien Delourme
- Neurology Department, Hôpital Pasteur 2, Centre Hospitalier Universitaire de Nice, Nice, France
| | - Jérôme Honnorat
- French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, Lyon, France.,Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France
| | - Pierre Thomas
- Neurology Department, Hôpital Pasteur 2, Centre Hospitalier Universitaire de Nice, Nice, France
| | - Christine Lebrun-Frenay
- URRIS, Unité de Recherche Clinique Cote d'Azur-UR2CA, CRCSEP, Hôpital Pasteur 2, Centre Hospitalier Universitaire de Nice, Nice, France.,Neurology Department, Hôpital Pasteur 2, Centre Hospitalier Universitaire de Nice, Nice, France
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19
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Nguyen UT, Nguyen LTH, Kim BA, Choi MJ, Yang IJ, Shin HM. Natural Compound Mixture, Containing Emodin, Genipin, Chlorogenic Acid, Cimigenoside, and Ginsenoside Rb1, Ameliorates Psoriasis-Like Skin Lesions by Suppressing Inflammation and Proliferation in Keratinocytes. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2020; 2020:9416962. [PMID: 33149756 PMCID: PMC7603578 DOI: 10.1155/2020/9416962] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/16/2020] [Accepted: 10/07/2020] [Indexed: 01/13/2023]
Abstract
Herbal combinations of Rhei Radix et Rhizoma, Gardeniae Fructus, Cimicifugae Rhizoma, and Ginseng Radix have been used in traditional formulas to treat the symptoms of heat and dryness. This study investigated the therapeutic effects of a natural compound mixture (PSM) of these herbal combinations, containing emodin, genipin, chlorogenic acid, cimigenoside, and ginsenoside Rb1, for the treatment of psoriasis and its underlying molecular mechanisms. PSM was applied topically to the dorsal skin lesions of imiquimod- (IMQ-) induced C57BL/6 mice, and the expression of the proinflammatory mediators was investigated. The topical application of 1% PSM reduced psoriasis-like symptoms in IMQ-induced C57BL/6 mice significantly. PSM also attenuated the production of IFN-γ, IL-1β, and IL-6 in skin lesions. Histological analysis showed that PSM had antipsoriatic effects by reducing the lesional epidermal thickness. Either M5 (IL-1α, IL-17A, IL-22, oncostatin M, and TNF-α, 10 ng/ml each) or IL-22- (100 ng/ml) stimulated HaCaT cells were used to examine the efficacy and underlying mechanism of PSM. In M5-stimulated HaCaT cells, PSM inhibited the production of C-X-C motif chemokine ligand (CXCL) 10 and C-C motif chemokine ligand (CCL) 20 effectively. Moreover, compared to the use of a single compound, it had synergistic inhibitory effects in CXCL8 production. PSM suppressed the phosphorylation of ERK1/2, p38, and STAT3 signaling pathways in M5-stimulated HaCaT cells. Furthermore, PSM reduced the proliferation rate and K16 and K17 expressions in IL-22-stimulated HaCaT cells by inhibiting the Akt/mTOR signaling pathway. These results suggest that PSM may have a therapeutic potential in the treatment of psoriasis lesions.
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Affiliation(s)
- Uy Thai Nguyen
- Department of Physiology, College of Korean Medicine Dongguk University, Gyeongju 38066, Republic of Korea
| | - Ly Thi Huong Nguyen
- Department of Physiology, College of Korean Medicine Dongguk University, Gyeongju 38066, Republic of Korea
| | - Bo-Ae Kim
- Division of Biomedicinal & Cosmetics, College of Sciences & Technology, Mokwon University, Daejeon 302-729, Republic of Korea
| | - Min-Jin Choi
- Department of Physiology, College of Korean Medicine Dongguk University, Gyeongju 38066, Republic of Korea
| | - In-Jun Yang
- Department of Physiology, College of Korean Medicine Dongguk University, Gyeongju 38066, Republic of Korea
| | - Heung-Mook Shin
- Department of Physiology, College of Korean Medicine Dongguk University, Gyeongju 38066, Republic of Korea
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20
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Abstract
PURPOSE OF REVIEW Chemokines are a large group of low molecular weight cytokines that attract and activate leukocytes throughout the body and therefore have a key role in the framework of late-phase allergic responses. The purpose of this article is to provide an overview of the main chemokines involved in allergic conjunctivitis, their primary functions and their physiological roles, and therapies targeted at chemokines and their receptors for ocular allergic diseases. RECENT FINDINGS In recent years, there have been considerable advances in the understanding of ocular pathophysiology of ocular surface inflammatory diseases including both allergic eye diseases and dry eye syndrome. Several therapies being developed for dry eye inflammation are recognized as possible therapies for ocular allergic diseases as there are often common chemokines involved in both disease spectra. SUMMARY Chemokines represent an integral part of the late-phase cascade of ocular allergic inflammation. A deep understanding of specific chemokines and their interactions will help in targeting therapies to effectively manage ocular clinical findings and symptoms of allergic eye disease.
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21
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Heo YJ, Choi SE, Lee N, Jeon JY, Han SJ, Kim DJ, Kang Y, Lee KW, Kim HJ. CCL20 induced by visfatin in macrophages via the NF-κB and MKK3/6-p38 signaling pathways contributes to hepatic stellate cell activation. Mol Biol Rep 2020; 47:4285-4293. [PMID: 32418112 PMCID: PMC7295719 DOI: 10.1007/s11033-020-05510-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 05/08/2020] [Indexed: 12/16/2022]
Abstract
Chemokines interact with hepatic resident cells during inflammation and fibrosis. CC chemokine ligand (CCL) 20 has been reported to be important in inflammation and fibrosis in the liver. We hypothesized that visfatin, an adipocytokine, could play a role in hepatic fibrosis via CCL20. We investigated the effect of visfatin on CCL20 in THP-1 human promonocytic cells and examined the molecular mechanisms involved. Following treatment of THP-1 cells with visfatin, CCL20 expression and secretion were assessed. We assessed the intracellular signaling molecules IKK/NF-κB, JAK2/STAT3, MAPKs, and MKK3/6 by western blotting. We treated THP-1 cells with visfatin and signaling inhibitors, and examined CCL20 mRNA and protein levels. To investigate the effect of visfatin-induced CCL20 expression in hepatic stellate cells (HSCs), LX-2 cells were co-cultured with the culture supernatant of THP-1 cells with or without anti-CCL20 neutralizing antibodies, and fibrosis markers were examined by RT-PCR and immunoblotting. In THP-1 cells, visfatin increased the CCL20 mRNA and protein levels. visfatin increased the activities of the NF-κB, p38, and MLK3/6 signaling pathways but not those of the JAK2/STAT3 and ERK pathways. Visfatin treatment together with an NF-κB, p38, or MLK3 inhibitor reduced the mRNA and protein levels of CCL20. The visfatin-induced CCL20 increased the expression of fibrosis markers and CCR6 in HSCs. Following neutralization of CCL20, the levels of fibrosis markers and CCR6 were decreased. Visfatin increases the expression of CCL20 via the NF-κB and MKK3/6-p38 signaling pathways in macrophages, and visfatin-induced CCL20 expression promotes the fibrosis markers in HSCs.
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Affiliation(s)
- Yu Jung Heo
- Department of Biomedical Sciences, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Sung-E Choi
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Nami Lee
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 206, World cup-ro, Yeongtong-gu, Suwon, 16499, Republic of Korea
| | - Ja Young Jeon
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 206, World cup-ro, Yeongtong-gu, Suwon, 16499, Republic of Korea
| | - Seung Jin Han
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 206, World cup-ro, Yeongtong-gu, Suwon, 16499, Republic of Korea
| | - Dae Jung Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 206, World cup-ro, Yeongtong-gu, Suwon, 16499, Republic of Korea
| | - Yup Kang
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Kwan Woo Lee
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 206, World cup-ro, Yeongtong-gu, Suwon, 16499, Republic of Korea
| | - Hae Jin Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 206, World cup-ro, Yeongtong-gu, Suwon, 16499, Republic of Korea.
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22
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Sato S, Zhang XK, Temmoku J, Fujita Y, Matsuoka N, Yashiro-Furuya M, Asano T, Kobayashi H, Watanabe H, Migita K. Ets Family Transcription Factor Fli-1 Promotes Leukocyte Recruitment and Production of IL-17A in the MRL/Lpr Mouse Model of Lupus Nephritis. Cells 2020; 9:cells9030714. [PMID: 32183259 PMCID: PMC7140643 DOI: 10.3390/cells9030714] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 03/08/2020] [Accepted: 03/13/2020] [Indexed: 12/20/2022] Open
Abstract
The transcription factor Friend leukemia integration 1 (Fli-1) regulates the expression of numerous cytokines and chemokines and alters the progression of lupus nephritis in humans and in the MRL/MpJ-Faslpr (MRL/lpr) mouse model. Th17-mediated immune responses are notably important as they promote ongoing inflammation. The purpose of this study is to determine the impact of Fli-1 on expression of interleukin-17A (IL-17A) and the infiltration of immune cells into the kidney. IL-17A concentrations were measured by ELISA in sera collected from MRL/lpr Fli-1-heterozygotes (Fli-1+/−) and MRL/lpr Fli-1+/+ control littermates. Expression of IL-17A and related proinflammatory mediators was measured by real-time polymerase chain reaction (RT-PCR). Immunofluorescence staining was performed on renal tissue from MRL/lpr Fli-1+/− and control littermates using anti-CD3, anti-CD4, and anti-IL-17A antibodies to detect Th17 cells and anti-CCL20 and anti-CD11b antibodies to identify CCL20+ monocytes. The expression of IL-17A in renal tissue was significantly reduced; this was accompanied by decreases in expression of IL-6, signal transducer and activator of transcription 3 (STAT3), and IL-1β. Likewise, we detected fewer CD3+IL-17+ and CD4+IL-17+ cells in renal tissue of MLR/lpr Fli-1+/− mice and significantly fewer CCL20+CD11b+ monocytes. In conclusion, partial deletion of Fli-1 has a profound impact on IL-17A expression and on renal histopathology in the MRL/lpr mouse.
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Affiliation(s)
- Shuzo Sato
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan; (J.T.); (Y.F.); (N.M.); (M.Y.-F.); (T.A.); (H.K.); (H.W.); (K.M.)
- Correspondence: (S.S.); (X.K.Z.); Tel.: +81-24-547-1171 (S.S.); +1-843-792-1991 (X.K.Z.); Fax: +81-24-547-1172 (S.S.); +1-843-792-7121 (X.K.Z.)
| | - Xian K. Zhang
- Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
- Correspondence: (S.S.); (X.K.Z.); Tel.: +81-24-547-1171 (S.S.); +1-843-792-1991 (X.K.Z.); Fax: +81-24-547-1172 (S.S.); +1-843-792-7121 (X.K.Z.)
| | - Jumpei Temmoku
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan; (J.T.); (Y.F.); (N.M.); (M.Y.-F.); (T.A.); (H.K.); (H.W.); (K.M.)
| | - Yuya Fujita
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan; (J.T.); (Y.F.); (N.M.); (M.Y.-F.); (T.A.); (H.K.); (H.W.); (K.M.)
| | - Naoki Matsuoka
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan; (J.T.); (Y.F.); (N.M.); (M.Y.-F.); (T.A.); (H.K.); (H.W.); (K.M.)
| | - Makiko Yashiro-Furuya
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan; (J.T.); (Y.F.); (N.M.); (M.Y.-F.); (T.A.); (H.K.); (H.W.); (K.M.)
| | - Tomoyuki Asano
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan; (J.T.); (Y.F.); (N.M.); (M.Y.-F.); (T.A.); (H.K.); (H.W.); (K.M.)
| | - Hiroko Kobayashi
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan; (J.T.); (Y.F.); (N.M.); (M.Y.-F.); (T.A.); (H.K.); (H.W.); (K.M.)
| | - Hiroshi Watanabe
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan; (J.T.); (Y.F.); (N.M.); (M.Y.-F.); (T.A.); (H.K.); (H.W.); (K.M.)
| | - Kiyoshi Migita
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan; (J.T.); (Y.F.); (N.M.); (M.Y.-F.); (T.A.); (H.K.); (H.W.); (K.M.)
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23
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Sanderford V, Barna BP, Barrington RA, Malur A, Mohan A, Leffler N, Soliman E, Thomassen MJ. PPARγ Deficiency in Carbon Nanotube-elicited Granulomatous Inflammation Promotes a Th17 Response to a Microbial Antigen. JOURNAL OF NANOMEDICINE & NANOTECHNOLOGY 2020; 11:541. [PMID: 32405439 PMCID: PMC7219023 DOI: 10.35248/2157-7439.20.11.541] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The pathological consequences of interaction between environmental carbon pollutants and microbial antigens have not been fully explored. We developed a murine model of multi-wall carbon nanotube (MWCNT)-elicited granulomatous disease which bears a striking resemblance to sarcoidosis, a human granulomatous disease. Because of reports describing lymphocyte reactivity to mycobacterial antigens in sarcoidosis patients, we hypothesized that addition of mycobacterial antigen (ESAT-6) to MWCNT might elicit activation in T cells. METHODS Macrophage-specific peroxisome-proliferator-activated receptor gamma (PPARγ) knock out (KO) mice were studied along with wild-type mice because our previous report indicated PPARγ deficiency in sarcoidosis alveolar macrophages. MWCNT+ESAT-6 were instilled into mice. Controls received vehicle (surfactant-PBS) or ESAT-6 and were evaluated 60 days post-instillation. As noted in our recent publication, lung tissues from PPARγ KO mice instilled with MWCNT+ESAT-6 yielded more intensive pathophysiology, with elevated fibrosis. RESULTS Inspection of mediastinal lymph nodes (MLN) revealed no granulomas but deposition of MWCNT. MLN cell counts were higher in PPARγ KO than in wild-type instilled with MWCNT+ESAT-6. Moreover, the CD4:CD8 T cell ratio, a major clinical metric for human disease, was increased in PPARγ KO mice. Bronchoalveolar lavage (BAL) cells from PPARγ KO mice instilled with MWCNT+ESAT-6 displayed increased Th17 cell markers (RORγt, IL-17A, CCR6) which associate with elevated fibrosis. CONCLUSION These findings suggest that PPARγ deficiency in macrophages may promote ESAT-6-associated T cell activation in the lung, and that the MWCNT+ESAT-6 model may offer new insights into pathways of lymphocyte-mediated sarcoidosis histopathology.
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Affiliation(s)
- Victoria Sanderford
- Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA
| | - Barbara P Barna
- Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA
| | - Robert A Barrington
- Department of Microbiology and Immunology, University of South Alabama, Mobile, AL, USA
| | - Anagha Malur
- Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA
| | - Arjun Mohan
- Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA
| | - Nancy Leffler
- Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA
| | - Eman Soliman
- Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Mary Jane Thomassen
- Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA
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Munjal A, Khandia R. Atherosclerosis: orchestrating cells and biomolecules involved in its activation and inhibition. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2019; 120:85-122. [PMID: 32085889 DOI: 10.1016/bs.apcsb.2019.11.002] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The term atherosclerosis refers to the condition of deposition of lipids and other substances in and on the artery walls, called as plaque that restricts the normal blood flow. The plaque may be stable or unstable in nature. Unstable plaque can burst and trigger clot formation adding further adversities. The process of plaque formation involves various stages including fatty streak, intermediate or fibro-fatty lesion and advanced lesion. The cells participating in the formation of atherosclerotic plaque include endothelial cells, vascular smooth muscle cells (VSMC), monocytes, monocytes derived macrophages, macrophages and dendritic cells and regulatory T cells (TREG). The role of a variety of cytokines and chemokines have been studied which either help in progression of atherosclerotic plaque or vice versa. The cytokines involved in atherosclerotic plaque formation include IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, IL-18, IL-20, IL-25, IL-27, IL-33, IL-37, TNF-α, TGF-β and IFN-γ; whereas amongst the chemokines (family of small cytokines) are CCL2, CCL3, CXCL4, CCL5, CXCL1, CX3CL1, CCL17, CXCL8, CXCL10, CCL20, CCL19 and CCL21 and macrophage migration-inhibitory factor. These are involved in the atherosclerosis advancements, whereas the chemokine CXCL12 is play atheroprotective roles. Apart this, contradictory functions have been documented for few other chemokines such as CXCL16. Since the cytokines and chemokines are amongst the key molecules involved in orchestrating the atherosclerosis advancements, targeting them might be an effective strategy to encumber the atherosclerotic progression. Blockage of cytokines and chemokines via the means of broad-spectrum inhibitors, neutralizing antibodies, usage of decoy receptors or RNA interference have been proved to be useful intervention against atherosclerosis.
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Affiliation(s)
- Ashok Munjal
- Department of Genetics, Barkatullah University, Bhopal, MP, India
| | - Rekha Khandia
- Department of Genetics, Barkatullah University, Bhopal, MP, India
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25
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Zeng C, Chen L, Chen B, Cai Y, Li P, Yan L, Zeng D. Th17 cells were recruited and accumulated in the cerebrospinal fluid and correlated with the poor prognosis of anti-NMDAR encephalitis. Acta Biochim Biophys Sin (Shanghai) 2018; 50:1266-1273. [PMID: 30418472 DOI: 10.1093/abbs/gmy137] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Indexed: 12/24/2022] Open
Abstract
Anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis is an autoimmune disorder characterized by memory deficits, psychiatric symptoms, and autonomic instability. The lack of suitable biomarkers targeting anti-NMDAR encephalitis makes the immunotherapy and prognosis challenging. In this study, we found that the Th17 cells were significantly accumulated in the cerebrospinal fluid (CSF) of anti-NMDAR encephalitis patients than that of control individuals. The concentration of the cytokines and chemokines including interleukin (IL)-1β, IL-17, IL-6, and CXCL-13 were significantly increased in the CSF of anti-NMDAR encephalitis patients. IL-6 and IL-17 were found to promote the differentiation of CD4+ T cells into Th17 lineage. The chemotaxis assay showed that CCL20 and CCL22 play essential roles in the migration of Th17 cells. Notably, the correlation between the expression of IL-17 and the outcome of anti-NMDAR encephalitis patients was analyzed. The data showed that high level of IL-17 was significantly correlated with the limited response to the treatment and relapse of anti-NMDAR encephalitis patients. Our results suggested the potential important involvement of IL-17 in anti-NMDAR encephalitis.
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Affiliation(s)
- Chaosheng Zeng
- Department of Neurology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Lin Chen
- Department of Neurology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Bocan Chen
- Department of Neurology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Yi Cai
- Department of Neurology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Pengxiang Li
- Department of Neurology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Limin Yan
- Department of Neurology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Dehua Zeng
- Department of Neurology, Haikou People’s Hospital, Haikou, China
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Skovdahl HK, Damås JK, Granlund AVB, Østvik AE, Doseth B, Bruland T, Mollnes TE, Sandvik AK. C-C Motif Ligand 20 (CCL20) and C-C Motif Chemokine Receptor 6 (CCR6) in Human Peripheral Blood Mononuclear Cells: Dysregulated in Ulcerative Colitis and a Potential Role for CCL20 in IL-1β Release. Int J Mol Sci 2018; 19:ijms19103257. [PMID: 30347808 PMCID: PMC6214005 DOI: 10.3390/ijms19103257] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 09/21/2018] [Accepted: 10/12/2018] [Indexed: 12/16/2022] Open
Abstract
The chemokine C-C motif ligand 20 (CCL20) is increased in the colonic mucosa during active inflammatory bowel disease (IBD) and can be found both in the epithelium and immune cells in the lamina propria. The present study investigated CCL20 and C-C motif Chemokine Receptor 6 (CCR6) in peripheral blood mononuclear cells (PBMCs) (n = 40) from IBD patients and healthy controls, to identify inductors of CCL20 release encountered in a local proinflammatory environment. CCL20 release from PBMCs was increased when activating TLR2/1 or NOD2, suggesting that CCL20 is part of a first line response to danger-associated molecular patterns also in immune cells. Overall, ulcerative colitis (UC) had a significantly stronger CCL20 release than Crohn’s disease (CD) (+242%, p < 0.01), indicating that the CCL20-CCR6 axis may be more involved in UC. The CCL20 receptor CCR6 is essential for the chemotactic function of CCL20. UC with active inflammation had significantly decreased CCR6 expression and a reduction in CCR6+ cells in circulation, indicating chemoattraction of CCR6+ cells from circulation towards peripheral tissues. We further examined CCL20 induced release of cytokines from PBMCs. Stimulation with CCL20 combined with TNF increased IL-1β release from PBMCs. By attracting additional immune cells, as well as inducing proinflammatory IL-1β release from immune cells, CCL20 may protract the inflammatory response in ulcerative colitis.
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Affiliation(s)
- Helene Kolstad Skovdahl
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology (NTNU), 7030 Trondheim, Norway.
- Department of Clinical and Molecular Medicine, NTNU, 7030 Trondheim, Norway.
| | - Jan Kristian Damås
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology (NTNU), 7030 Trondheim, Norway.
- Department of Clinical and Molecular Medicine, NTNU, 7030 Trondheim, Norway.
- Department of Infectious Diseases, St. Olav's University Hospital, 7030 Trondheim, Norway.
| | - Atle van Beelen Granlund
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology (NTNU), 7030 Trondheim, Norway.
- Department of Clinical and Molecular Medicine, NTNU, 7030 Trondheim, Norway.
| | - Ann Elisabet Østvik
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology (NTNU), 7030 Trondheim, Norway.
- Department of Clinical and Molecular Medicine, NTNU, 7030 Trondheim, Norway.
- Department of Gastroenterology and Hepatology, St. Olav's University Hospital, 7030 Trondheim, Norway.
| | - Berit Doseth
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology (NTNU), 7030 Trondheim, Norway.
- Department of Clinical and Molecular Medicine, NTNU, 7030 Trondheim, Norway.
- Clinic of Medicine, St. Olav's University Hospital, 7030 Trondheim, Norway.
| | - Torunn Bruland
- Department of Clinical and Molecular Medicine, NTNU, 7030 Trondheim, Norway.
- Clinic of Medicine, St. Olav's University Hospital, 7030 Trondheim, Norway.
| | - Tom Eirik Mollnes
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology (NTNU), 7030 Trondheim, Norway.
- Department of Immunology, Oslo University Hospital and University of Oslo, 0372 Oslo, Norway.
- Research Laboratory, Department of Laboratory Medicine, Nordland Hospital, 8005 Bodo, Norway.
- K.G. Jebsen TREC, University of Tromsø, 9037 Tromsø, Norway.
| | - Arne Kristian Sandvik
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology (NTNU), 7030 Trondheim, Norway.
- Department of Clinical and Molecular Medicine, NTNU, 7030 Trondheim, Norway.
- Department of Gastroenterology and Hepatology, St. Olav's University Hospital, 7030 Trondheim, Norway.
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Nastase MV, Zeng-Brouwers J, Beckmann J, Tredup C, Christen U, Radeke HH, Wygrecka M, Schaefer L. Biglycan, a novel trigger of Th1 and Th17 cell recruitment into the kidney. Matrix Biol 2018; 68-69:293-317. [DOI: 10.1016/j.matbio.2017.12.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Revised: 12/10/2017] [Accepted: 12/10/2017] [Indexed: 12/11/2022]
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Saini C, Siddiqui A, Ramesh V, Nath I. Leprosy Reactions Show Increased Th17 Cell Activity and Reduced FOXP3+ Tregs with Concomitant Decrease in TGF-β and Increase in IL-6. PLoS Negl Trop Dis 2016; 10:e0004592. [PMID: 27035913 PMCID: PMC4818038 DOI: 10.1371/journal.pntd.0004592] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 03/09/2016] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND 50% of leprosy patients suffer from episodes of Type 1/ reversal reactions (RR) and Type 2/ Erythema Nodosum Leprosum (ENL) reactions which lead to morbidity and nerve damage. CD4+ subsets of Th17 cells and CD25+FOXP3+ regulatory T cells (Tregs) have been shown to play a major role in disease associated immunopathology and in stable leprosy as reported by us and others. The aim of our study was to analyze their role in leprosy reactions. METHODOLOGY AND PRINCIPLE FINDINGS Quantitative reverse transcribed PCR (qPCR), flowcytometry and ELISA were used to respectively investigate gene expression, cell phenotypes and supernatant levels of cytokines in antigen stimulated PBMC cultures in patients with stable disease and those undergoing leprosy reactions. Both types of reactions are associated with significant increase of Th17 cells and associated cytokines IL-17A, IL-17F, IL-21, IL-23 and chemokines CCL20, CCL22 as compared to matching stable forms of leprosy. Concurrently patients in reactions show reduction in FOXP3+ Treg cells as well as reduction in TGF-β and increase in IL-6. Moreover, expression of many T cell markers, cytokines, chemokines and signaling factors were observed to be increased in RR as compared to ENL reaction patients. CONCLUSIONS Patients with leprosy reactions show an imbalance in Th17 and Treg populations. The reduction in Treg suppressor activity is associated withhigherTh17cell activity. The combined effect of reduced TGF-β and enhanced IL-6, IL-21 cytokines influence the balance between Th17 or Treg cells in leprosy reactions as reported in the murine models and autoimmune diseases. The increase in Th17 cell associated cytokines may contribute to lesional inflammation.
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Affiliation(s)
- Chaman Saini
- National Institute of Pathology (ICMR) Safdarjung Hospital Campus, New Delhi, India
| | | | | | - Indira Nath
- National Institute of Pathology (ICMR) Safdarjung Hospital Campus, New Delhi, India
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Roberts CA, Dickinson AK, Taams LS. The Interplay Between Monocytes/Macrophages and CD4(+) T Cell Subsets in Rheumatoid Arthritis. Front Immunol 2015; 6:571. [PMID: 26635790 PMCID: PMC4652039 DOI: 10.3389/fimmu.2015.00571] [Citation(s) in RCA: 169] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 10/26/2015] [Indexed: 12/24/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by inflammation of the synovial lining (synovitis). The inflammation in the RA joint is associated with and driven by immune cell infiltration, synovial hyperproliferation, and excessive production of proinflammatory mediators, such as tumor necrosis factor α (TNFα), interferon γ (IFNγ), interleukin (IL)-1β, IL-6, and IL-17, eventually resulting in damage to the cartilage and underlying bone. The RA joint harbors a wide range of immune cell types, including monocytes, macrophages, and CD4(+) T cells (both proinflammatory and regulatory). The interplay between CD14(+) myeloid cells and CD4(+) T cells can significantly influence CD4(+) T cell function, and conversely, effector vs. regulatory CD4(+) T cell subsets can exert profound effects on monocyte/macrophage function. In this review, we will discuss how the interplay between CD4(+) T cells and monocytes/macrophages may contribute to the immunopathology of RA.
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Affiliation(s)
- Ceri A Roberts
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), Division of Immunology, Infection and Inflammatory Disease, King's College London , London , UK
| | - Abigail K Dickinson
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), Division of Immunology, Infection and Inflammatory Disease, King's College London , London , UK
| | - Leonie S Taams
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), Division of Immunology, Infection and Inflammatory Disease, King's College London , London , UK
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30
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Lahoti TS, Boyer JA, Kusnadi A, Muku GE, Murray IA, Perdew GH. Aryl Hydrocarbon Receptor Activation Synergistically Induces Lipopolysaccharide-Mediated Expression of Proinflammatory Chemokine (c-c motif) Ligand 20. Toxicol Sci 2015; 148:229-40. [PMID: 26259605 DOI: 10.1093/toxsci/kfv178] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
The Ah receptor (AHR) is directly involved in the regulation of both innate and adaptive immunity. However, these activities are poorly understood at the level of gene regulation. The chemokine (c-c motif) ligand 20 (CCL20) plays a nonredundant role in the chemoattraction of C-C motif receptor 6 expressing cells (eg, T cells and others). A survey of promoter regions of chemokine genes revealed that there are several putative dioxin responsive elements in the mouse Ccl20 promoter. The addition of an AHR agonist along with lipopolysaccharide (LPS) to cultured primary peritoneal macrophages results in synergistic induction of both Ccl20 mRNA and protein, compared with each compound alone. Through the use of macrophage cultures derived from Ahr(-) (/) (-) and Ahr(nls/nls) mice, it was established that expression of the AHR and its ability to translocate into the nucleus are necessary for AHR ligand-mediated synergistic induction of Ccl20. Gel shift analysis determined that a potent tandem AHR binding site ~3.1 kb upstream from the transcriptional start site can efficiently bind the AHR/ARNT (aryl hydrocarbon receptor/AHR nuclear translocator) heterodimer upon activation with a number of AHR agonists. Furthermore, studies reveal that LPS increases AHR levels on the Ccl20 promoter while decreasing HDAC1 occupancy. The level of Ccl20 constitutive expression in the colon is greatly attenuated in Ahr(-) (/) (-) mice. These studies suggest that the presence of AHR ligands during localized inflammation may augment chemokine expression, thus participating in the overall response to pathogens.
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Affiliation(s)
- Tejas S Lahoti
- Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Penn State University, University Park, Pennsylvania 16802
| | - Jacob A Boyer
- Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Penn State University, University Park, Pennsylvania 16802
| | - Ann Kusnadi
- Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Penn State University, University Park, Pennsylvania 16802
| | - Gulsum E Muku
- Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Penn State University, University Park, Pennsylvania 16802
| | - Iain A Murray
- Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Penn State University, University Park, Pennsylvania 16802
| | - Gary H Perdew
- Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Penn State University, University Park, Pennsylvania 16802
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Wang YL, Fang M, Wang XM, Liu WY, Zheng YJ, Wu XB, Tao R. Proinflammatory effects and molecular mechanisms of interleukin-17 in intestinal epithelial cell line HT-29. World J Gastroenterol 2014; 20:17924-17931. [PMID: 25548490 PMCID: PMC4273142 DOI: 10.3748/wjg.v20.i47.17924] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2014] [Revised: 08/24/2014] [Accepted: 10/21/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the proinflammatory effects and molecular mechanisms of interleukin (IL)-17 in intestinal epithelial cell line HT-29. METHODS HT-29 cells were cultured with IL-17, tumor necrosis factor (TNF)-α, or the combination of both IL-17 and TNF-α. Real-time PCR and Western blot were used to measure the gene expression levels of neutrophil chemokines CXCL1, CXCL2, CXCL5, CXCL6, IL-8 and TH-17 cell chemokine CCL20, the phosphorylation levels of p38 and TNF-α, and the expression level of IL-8, after using the p38 inhibitor in HT-29 cells. The stable Act1 knockdown HT-29 cell line was established to further test the phosphorylation changes of p38, after using IL-17 and TNF-α. RESULTS After HT-29 cells were cultured with IL-17 and TNF-α, the expression levels of neutrophil chemokines (CXCL1, CXCL2, CXCL5, CXCL6, IL-8) and Th17 chemokine (CCL20) significantly improved (24.96 ± 2.53, 28.47 ± 2.87, 38.08 ± 2.72, 33.47 ± 2.41, 31.7 ± 2.38, 44.37 ± 2.73, respectively), and the differences were all statistically significant (P < 0.01). Western blot results showed that IL-17 obviously enhanced the phosphorylation level of p38, which was induced by TNF-α. Compared with the control group, the expression level of IL-8 significantly declined (9.47 ± 1.36 vs 3.06 ± 0.67, P < 0.01) when TH-29 cells were cultured with IL-17 and TNF-α. p38 inhibition assay showed that the p38 pathway played an essential role in the inflammatory response induced by IL-17. p38 phosphorylation levels could not be changed after using IL-17 and TNF-α in the stable Act1 knockdown HT-29 cell line. CONCLUSION IL-17 significantly promoted the gene expression levels of TNF-α-induced neutrophil chemokines and Th17 cell chemokine. It is obvious that IL-17 and TNF-α have synergistic effects on p38.
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Al-Horani RA, Desai UR. Recent advances on plasmin inhibitors for the treatment of fibrinolysis-related disorders. Med Res Rev 2014; 34:1168-1216. [PMID: 24659483 PMCID: PMC8788159 DOI: 10.1002/med.21315] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/07/2023]
Abstract
Growing evidence suggests that plasmin is involved in a number of physiological processes in addition to its key role in fibrin cleavage. Plasmin inhibition is critical in preventing adverse consequences arising from plasmin overactivity, e.g., blood loss that may follow cardiac surgery. Aprotinin was widely used as an antifibrinolytic drug before its discontinuation in 2008. Tranexamic acid and ε-aminocaproic acid, two small molecule plasmin inhibitors, are currently used in the clinic. Several molecules have been designed utilizing covalent, but reversible, chemistry relying on reactive cyclohexanones, nitrile warheads, and reactive aldehyde peptidomimetics. Other major classes of plasmin inhibitors include the cyclic peptidomimetics and polypeptides of the Kunitz and Kazal-type. Allosteric inhibitors of plasmin have also been designed including small molecule lysine analogs that bind to plasmin's kringle domain(s) and sulfated glycosaminoglycan mimetics that bind to plasmin's catalytic domain. Plasmin inhibitors have also been explored for resolving other disease states including cell metastasis, cell proliferation, angiogenesis, and embryo implantation. This review highlights functional and structural aspects of plasmin inhibitors with the goal of advancing their design.
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Affiliation(s)
- Rami A Al-Horani
- Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia
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Bacterial siderophores that evade or overwhelm lipocalin 2 induce hypoxia inducible factor 1α and proinflammatory cytokine secretion in cultured respiratory epithelial cells. Infect Immun 2014; 82:3826-36. [PMID: 24980968 DOI: 10.1128/iai.01849-14] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Iron is essential for many cellular processes and is required by bacteria for replication. To acquire iron from the host, pathogenic Gram-negative bacteria secrete siderophores, including enterobactin (Ent). However, Ent is bound by the host protein lipocalin 2 (Lcn2), preventing bacterial reuptake of aferric or ferric Ent. Furthermore, the combination of Ent and Lcn2 (Ent+Lcn2) leads to enhanced secretion of interleukin-8 (IL-8) compared to that induced by either stimulus alone. Modified or structurally distinct siderophores, including yersiniabactin (Ybt) and glycosylated Ent (GlyEnt, or salmochelin), deliver iron to bacteria despite the presence of Lcn2. We hypothesized that the robust immune response to Ent and Lcn2 requires iron chelation rather than the Ent+Lcn2 complex itself and also can be stimulated by Lcn2-evasive siderophores. To test this hypothesis, cultured respiratory epithelial cells were stimulated with combinations of purified siderophores and Lcn2 and analyzed by gene expression microarrays, quantitative PCR, and cytokine immunoassays. Ent caused HIF-1α protein stabilization, induced the expression of genes regulated by hypoxia-inducible factor 1α (HIF-1α), and repressed genes involved in cell cycle and DNA replication, whereas Lcn2 induced expression of proinflammatory cytokines. Iron chelation by excess Ent or Ybt significantly increased Lcn2-induced secretion of IL-8, IL-6, and CCL20. Stabilization of HIF-1α was sufficient to enhance Lcn2-induced IL-6 secretion. These data indicate that respiratory epithelial cells can respond to bacterial siderophores that evade or overwhelm Lcn2 binding by increasing proinflammatory cytokine production.
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