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“Small” Intestinal Immunopathology Plays a “Big” Role in Lethal Cytokine Release Syndrome, and Its Modulation by Interferon-γ, IL-17A, and a Janus Kinase Inhibitor
Chimeric antigen receptor T cell (CART) therapy, administration of certain T cell-agonistic antibodies, immune check point inhibitors, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) and Toxic shock syndrome (TSS) caused by streptococcal as...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333770/ https://www.ncbi.nlm.nih.gov/pubmed/32676080 http://dx.doi.org/10.3389/fimmu.2020.01311 |
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author | Kale, Shiv D. Mehrkens, Brittney N. Stegman, Molly M. Kastelberg, Bridget Carnes, Henry McNeill, Rachel J. Rizzo, Amy Karyala, Saikumar V. Coutermarsh-Ott, Sheryl Fretz, Jackie A. Sun, Ying Koff, Jonathan L. Rajagopalan, Govindarajan |
author_facet | Kale, Shiv D. Mehrkens, Brittney N. Stegman, Molly M. Kastelberg, Bridget Carnes, Henry McNeill, Rachel J. Rizzo, Amy Karyala, Saikumar V. Coutermarsh-Ott, Sheryl Fretz, Jackie A. Sun, Ying Koff, Jonathan L. Rajagopalan, Govindarajan |
author_sort | Kale, Shiv D. |
collection | PubMed |
description | Chimeric antigen receptor T cell (CART) therapy, administration of certain T cell-agonistic antibodies, immune check point inhibitors, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) and Toxic shock syndrome (TSS) caused by streptococcal as well as staphylococcal superantigens share one common complication, that is T cell-driven cytokine release syndrome (CRS) accompanied by multiple organ dysfunction (MOD). It is not understood whether the failure of a particular organ contributes more significantly to the severity of CRS. Also not known is whether a specific cytokine or signaling pathway plays a more pathogenic role in precipitating MOD compared to others. As a result, there is no specific treatment available to date for CRS, and it is managed only symptomatically to support the deteriorating organ functions and maintain the blood pressure. Therefore, we used the superantigen-induced CRS model in HLA-DR3 transgenic mice, that closely mimics human CRS, to delineate the immunopathogenesis of CRS as well as to validate a novel treatment for CRS. Using this model, we demonstrate that (i) CRS is characterized by a rapid rise in systemic levels of several Th1/Th2/Th17/Th22 type cytokines within a few hours, followed by a quick decline. (ii) Even though multiple organs are affected, small intestinal immunopathology is the major contributor to mortality in CRS. (iii) IFN-γ deficiency significantly protected from lethal CRS by attenuating small bowel pathology, whereas IL-17A deficiency significantly increased mortality by augmenting small bowel pathology. (iv) RNA sequencing of small intestinal tissues indicated that IFN-γ-STAT1-driven inflammatory pathways combined with enhanced expression of pro-apoptotic molecules as well as extracellular matrix degradation contributed to small bowel pathology in CRS. These pathways were further enhanced by IL-17A deficiency and significantly down-regulated in mice lacking IFN-γ. (v) Ruxolitinib, a selective JAK-1/2 inhibitor, attenuated SAg-induced T cell activation, cytokine production, and small bowel pathology, thereby completely protecting from lethal CRS in both WT and IL-17A deficient HLA-DR3 mice. Overall, IFN-γ-JAK-STAT-driven pathways contribute to lethal small intestinal immunopathology in T cell-driven CRS. |
format | Online Article Text |
id | pubmed-7333770 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-73337702020-07-15 “Small” Intestinal Immunopathology Plays a “Big” Role in Lethal Cytokine Release Syndrome, and Its Modulation by Interferon-γ, IL-17A, and a Janus Kinase Inhibitor Kale, Shiv D. Mehrkens, Brittney N. Stegman, Molly M. Kastelberg, Bridget Carnes, Henry McNeill, Rachel J. Rizzo, Amy Karyala, Saikumar V. Coutermarsh-Ott, Sheryl Fretz, Jackie A. Sun, Ying Koff, Jonathan L. Rajagopalan, Govindarajan Front Immunol Immunology Chimeric antigen receptor T cell (CART) therapy, administration of certain T cell-agonistic antibodies, immune check point inhibitors, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) and Toxic shock syndrome (TSS) caused by streptococcal as well as staphylococcal superantigens share one common complication, that is T cell-driven cytokine release syndrome (CRS) accompanied by multiple organ dysfunction (MOD). It is not understood whether the failure of a particular organ contributes more significantly to the severity of CRS. Also not known is whether a specific cytokine or signaling pathway plays a more pathogenic role in precipitating MOD compared to others. As a result, there is no specific treatment available to date for CRS, and it is managed only symptomatically to support the deteriorating organ functions and maintain the blood pressure. Therefore, we used the superantigen-induced CRS model in HLA-DR3 transgenic mice, that closely mimics human CRS, to delineate the immunopathogenesis of CRS as well as to validate a novel treatment for CRS. Using this model, we demonstrate that (i) CRS is characterized by a rapid rise in systemic levels of several Th1/Th2/Th17/Th22 type cytokines within a few hours, followed by a quick decline. (ii) Even though multiple organs are affected, small intestinal immunopathology is the major contributor to mortality in CRS. (iii) IFN-γ deficiency significantly protected from lethal CRS by attenuating small bowel pathology, whereas IL-17A deficiency significantly increased mortality by augmenting small bowel pathology. (iv) RNA sequencing of small intestinal tissues indicated that IFN-γ-STAT1-driven inflammatory pathways combined with enhanced expression of pro-apoptotic molecules as well as extracellular matrix degradation contributed to small bowel pathology in CRS. These pathways were further enhanced by IL-17A deficiency and significantly down-regulated in mice lacking IFN-γ. (v) Ruxolitinib, a selective JAK-1/2 inhibitor, attenuated SAg-induced T cell activation, cytokine production, and small bowel pathology, thereby completely protecting from lethal CRS in both WT and IL-17A deficient HLA-DR3 mice. Overall, IFN-γ-JAK-STAT-driven pathways contribute to lethal small intestinal immunopathology in T cell-driven CRS. Frontiers Media S.A. 2020-06-26 /pmc/articles/PMC7333770/ /pubmed/32676080 http://dx.doi.org/10.3389/fimmu.2020.01311 Text en Copyright © 2020 Kale, Mehrkens, Stegman, Kastelberg, Carnes, McNeill, Rizzo, Karyala, Coutermarsh-Ott, Fretz, Sun, Koff and Rajagopalan. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Kale, Shiv D. Mehrkens, Brittney N. Stegman, Molly M. Kastelberg, Bridget Carnes, Henry McNeill, Rachel J. Rizzo, Amy Karyala, Saikumar V. Coutermarsh-Ott, Sheryl Fretz, Jackie A. Sun, Ying Koff, Jonathan L. Rajagopalan, Govindarajan “Small” Intestinal Immunopathology Plays a “Big” Role in Lethal Cytokine Release Syndrome, and Its Modulation by Interferon-γ, IL-17A, and a Janus Kinase Inhibitor |
title | “Small” Intestinal Immunopathology Plays a “Big” Role in Lethal Cytokine Release Syndrome, and Its Modulation by Interferon-γ, IL-17A, and a Janus Kinase Inhibitor |
title_full | “Small” Intestinal Immunopathology Plays a “Big” Role in Lethal Cytokine Release Syndrome, and Its Modulation by Interferon-γ, IL-17A, and a Janus Kinase Inhibitor |
title_fullStr | “Small” Intestinal Immunopathology Plays a “Big” Role in Lethal Cytokine Release Syndrome, and Its Modulation by Interferon-γ, IL-17A, and a Janus Kinase Inhibitor |
title_full_unstemmed | “Small” Intestinal Immunopathology Plays a “Big” Role in Lethal Cytokine Release Syndrome, and Its Modulation by Interferon-γ, IL-17A, and a Janus Kinase Inhibitor |
title_short | “Small” Intestinal Immunopathology Plays a “Big” Role in Lethal Cytokine Release Syndrome, and Its Modulation by Interferon-γ, IL-17A, and a Janus Kinase Inhibitor |
title_sort | “small” intestinal immunopathology plays a “big” role in lethal cytokine release syndrome, and its modulation by interferon-γ, il-17a, and a janus kinase inhibitor |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333770/ https://www.ncbi.nlm.nih.gov/pubmed/32676080 http://dx.doi.org/10.3389/fimmu.2020.01311 |
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