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Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model

Autoimmune diseases are driven largely by a pathogenic cytokine milieu produced by aberrantly activated lymphocytes. Many cytokines, including interferon gamma (IFN-γ), utilize the JAK/STAT pathway for signal propagation. Suppressor of Cytokine Signaling-1 (SOCS1) is an inducible, intracellular prot...

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Autores principales: Sharma, Jatin, Collins, Teresa D., Roach, Tracoyia, Mishra, Shiwangi, Lam, Brandon K., Mohamed, Zaynab Sidi, Veal, Antia E., Polk, Timothy B., Jones, Amari, Cornaby, Caleb, Haider, Mohammed I., Zeumer-Spataro, Leilani, Johnson, Howard M., Morel, Laurence M., Larkin, Joseph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973732/
https://www.ncbi.nlm.nih.gov/pubmed/33737712
http://dx.doi.org/10.1038/s41598-021-86017-4
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author Sharma, Jatin
Collins, Teresa D.
Roach, Tracoyia
Mishra, Shiwangi
Lam, Brandon K.
Mohamed, Zaynab Sidi
Veal, Antia E.
Polk, Timothy B.
Jones, Amari
Cornaby, Caleb
Haider, Mohammed I.
Zeumer-Spataro, Leilani
Johnson, Howard M.
Morel, Laurence M.
Larkin, Joseph
author_facet Sharma, Jatin
Collins, Teresa D.
Roach, Tracoyia
Mishra, Shiwangi
Lam, Brandon K.
Mohamed, Zaynab Sidi
Veal, Antia E.
Polk, Timothy B.
Jones, Amari
Cornaby, Caleb
Haider, Mohammed I.
Zeumer-Spataro, Leilani
Johnson, Howard M.
Morel, Laurence M.
Larkin, Joseph
author_sort Sharma, Jatin
collection PubMed
description Autoimmune diseases are driven largely by a pathogenic cytokine milieu produced by aberrantly activated lymphocytes. Many cytokines, including interferon gamma (IFN-γ), utilize the JAK/STAT pathway for signal propagation. Suppressor of Cytokine Signaling-1 (SOCS1) is an inducible, intracellular protein that regulates IFN-γ signaling by dampening JAK/STAT signaling. Using Fas deficient, MRL/MpJ-Fas(lpr)/J (MRL/lpr) mice, which develop lupus-like disease spontaneously, we tested the hypothesis that a peptide mimic of the SOCS1 kinase inhibitory region (SOCS1-KIR) would inhibit lymphocyte activation and modulate lupus-associated pathologies. Consistent with in vitro studies, SOCS1-KIR intraperitoneal administration reduced the frequency, activation, and cytokine production of memory CD8(+) and CD4(+) T lymphocytes within the peripheral blood, spleen, and lymph nodes. In addition, SOCS1-KIR administration reduced lymphadenopathy, severity of skin lesions, autoantibody production, and modestly reduced kidney pathology. On a cellular level, peritoneal SOCS1-KIR administration enhanced Foxp3 expression in total splenic and follicular regulatory T cells, reduced the effector memory/naïve T lymphocyte ratio for both CD4(+) and CD8(+) cells, and reduced the frequency of GL7(+) germinal center enriched B cells. Together, these data show that SOCS1-KIR treatment reduced auto-reactive lymphocyte effector functions and suggest that therapeutic targeting of the SOCS1 pathway through peptide administration may have efficacy in mitigating autoimmune pathologies.
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spelling pubmed-79737322021-03-19 Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model Sharma, Jatin Collins, Teresa D. Roach, Tracoyia Mishra, Shiwangi Lam, Brandon K. Mohamed, Zaynab Sidi Veal, Antia E. Polk, Timothy B. Jones, Amari Cornaby, Caleb Haider, Mohammed I. Zeumer-Spataro, Leilani Johnson, Howard M. Morel, Laurence M. Larkin, Joseph Sci Rep Article Autoimmune diseases are driven largely by a pathogenic cytokine milieu produced by aberrantly activated lymphocytes. Many cytokines, including interferon gamma (IFN-γ), utilize the JAK/STAT pathway for signal propagation. Suppressor of Cytokine Signaling-1 (SOCS1) is an inducible, intracellular protein that regulates IFN-γ signaling by dampening JAK/STAT signaling. Using Fas deficient, MRL/MpJ-Fas(lpr)/J (MRL/lpr) mice, which develop lupus-like disease spontaneously, we tested the hypothesis that a peptide mimic of the SOCS1 kinase inhibitory region (SOCS1-KIR) would inhibit lymphocyte activation and modulate lupus-associated pathologies. Consistent with in vitro studies, SOCS1-KIR intraperitoneal administration reduced the frequency, activation, and cytokine production of memory CD8(+) and CD4(+) T lymphocytes within the peripheral blood, spleen, and lymph nodes. In addition, SOCS1-KIR administration reduced lymphadenopathy, severity of skin lesions, autoantibody production, and modestly reduced kidney pathology. On a cellular level, peritoneal SOCS1-KIR administration enhanced Foxp3 expression in total splenic and follicular regulatory T cells, reduced the effector memory/naïve T lymphocyte ratio for both CD4(+) and CD8(+) cells, and reduced the frequency of GL7(+) germinal center enriched B cells. Together, these data show that SOCS1-KIR treatment reduced auto-reactive lymphocyte effector functions and suggest that therapeutic targeting of the SOCS1 pathway through peptide administration may have efficacy in mitigating autoimmune pathologies. Nature Publishing Group UK 2021-03-18 /pmc/articles/PMC7973732/ /pubmed/33737712 http://dx.doi.org/10.1038/s41598-021-86017-4 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Sharma, Jatin
Collins, Teresa D.
Roach, Tracoyia
Mishra, Shiwangi
Lam, Brandon K.
Mohamed, Zaynab Sidi
Veal, Antia E.
Polk, Timothy B.
Jones, Amari
Cornaby, Caleb
Haider, Mohammed I.
Zeumer-Spataro, Leilani
Johnson, Howard M.
Morel, Laurence M.
Larkin, Joseph
Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model
title Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model
title_full Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model
title_fullStr Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model
title_full_unstemmed Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model
title_short Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model
title_sort suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the mrl/lpr mouse autoimmune model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973732/
https://www.ncbi.nlm.nih.gov/pubmed/33737712
http://dx.doi.org/10.1038/s41598-021-86017-4
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