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

Abstract 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, intracell...

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Autores principales:	Jatin Sharma, Teresa D. Collins, Tracoyia Roach, Shiwangi Mishra, Brandon K. Lam, Zaynab Sidi Mohamed, Antia E. Veal, Timothy B. Polk, Amari Jones, Caleb Cornaby, Mohammed I. Haider, Leilani Zeumer-Spataro, Howard M. Johnson, Laurence M. Morel, Joseph Larkin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/342a0706da1e4e82ad0f8fd96bbb0a38
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spelling	oai:doaj.org-article:342a0706da1e4e82ad0f8fd96bbb0a382021-12-02T17:04:59ZSuppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model10.1038/s41598-021-86017-42045-2322https://doaj.org/article/342a0706da1e4e82ad0f8fd96bbb0a382021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86017-4https://doaj.org/toc/2045-2322Abstract 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-Faslpr/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.Jatin SharmaTeresa D. CollinsTracoyia RoachShiwangi MishraBrandon K. LamZaynab Sidi MohamedAntia E. VealTimothy B. PolkAmari JonesCaleb CornabyMohammed I. HaiderLeilani Zeumer-SpataroHoward M. JohnsonLaurence M. MorelJoseph LarkinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jatin Sharma Teresa D. Collins Tracoyia Roach Shiwangi Mishra Brandon K. Lam Zaynab Sidi Mohamed Antia E. Veal Timothy B. Polk Amari Jones Caleb Cornaby Mohammed I. Haider Leilani Zeumer-Spataro Howard M. Johnson Laurence M. Morel Joseph Larkin Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model
description	Abstract 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-Faslpr/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.
format	article
author	Jatin Sharma Teresa D. Collins Tracoyia Roach Shiwangi Mishra Brandon K. Lam Zaynab Sidi Mohamed Antia E. Veal Timothy B. Polk Amari Jones Caleb Cornaby Mohammed I. Haider Leilani Zeumer-Spataro Howard M. Johnson Laurence M. Morel Joseph Larkin
author_facet	Jatin Sharma Teresa D. Collins Tracoyia Roach Shiwangi Mishra Brandon K. Lam Zaynab Sidi Mohamed Antia E. Veal Timothy B. Polk Amari Jones Caleb Cornaby Mohammed I. Haider Leilani Zeumer-Spataro Howard M. Johnson Laurence M. Morel Joseph Larkin
author_sort	Jatin Sharma
title	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_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_sort	suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the mrl/lpr mouse autoimmune model
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/342a0706da1e4e82ad0f8fd96bbb0a38
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Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model

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