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cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE

Detection of DNA is an important determinant of host-defense but also a driver of autoinflammatory and autoimmune diseases. Failure to degrade self-DNA in DNAseII or III(TREX1)-deficient mice results in activation of the cGAS-STING pathway. Deficiency of cGAS or STING in these models ameliorates dis...

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Autores principales: Motwani, Mona, McGowan, Jason, Antonovitch, Jennifer, Gao, Kevin MingJie, Jiang, Zhaozhao, Sharma, Shruti, Baltus, Gretchen A., Nickerson, Kevin M., Marshak-Rothstein, Ann, Fitzgerald, Katherine A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040952/
https://www.ncbi.nlm.nih.gov/pubmed/33854495
http://dx.doi.org/10.3389/fimmu.2021.605930
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author Motwani, Mona
McGowan, Jason
Antonovitch, Jennifer
Gao, Kevin MingJie
Jiang, Zhaozhao
Sharma, Shruti
Baltus, Gretchen A.
Nickerson, Kevin M.
Marshak-Rothstein, Ann
Fitzgerald, Katherine A.
author_facet Motwani, Mona
McGowan, Jason
Antonovitch, Jennifer
Gao, Kevin MingJie
Jiang, Zhaozhao
Sharma, Shruti
Baltus, Gretchen A.
Nickerson, Kevin M.
Marshak-Rothstein, Ann
Fitzgerald, Katherine A.
author_sort Motwani, Mona
collection PubMed
description Detection of DNA is an important determinant of host-defense but also a driver of autoinflammatory and autoimmune diseases. Failure to degrade self-DNA in DNAseII or III(TREX1)-deficient mice results in activation of the cGAS-STING pathway. Deficiency of cGAS or STING in these models ameliorates disease manifestations. However, the contribution of the cGAS-STING pathway, relative to endosomal TLRs, in systemic lupus erythematosus (SLE) is controversial. In fact, STING deficiency failed to rescue, and actually exacerbated, disease manifestations in Fas-deficient SLE-prone mice. We have now extended these observations to a chronic model of SLE induced by the i.p. injection of TMPD (pristane). We found that both cGAS- and STING-deficiency not only failed to rescue mice from TMPD-induced SLE, but resulted in increased autoantibody production and higher proteinuria levels compared to cGAS STING sufficient mice. Further, we generated cGAS(KO)Fas(lpr) mice on a pure MRL/Fas(lpr) background using Crispr/Cas9 and found slightly exacerbated, and not attenuated, disease. We hypothesized that the cGAS-STING pathway constrains TLR activation, and thereby limits autoimmune manifestations in these two models. Consistent with this premise, mice lacking cGAS and Unc93B1 or STING and Unc93B1 developed minimal systemic autoimmunity as compared to cGAS or STING single knock out animals. Nevertheless, TMPD-driven lupus in B6 mice was abrogated upon AAV-delivery of DNAse I, implicating a DNA trigger. Overall, this study demonstrated that the cGAS-STING pathway does not promote systemic autoimmunity in murine models of SLE. These data have important implications for cGAS-STING-directed therapies being developed for the treatment of systemic autoimmunity.
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spelling pubmed-80409522021-04-13 cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE Motwani, Mona McGowan, Jason Antonovitch, Jennifer Gao, Kevin MingJie Jiang, Zhaozhao Sharma, Shruti Baltus, Gretchen A. Nickerson, Kevin M. Marshak-Rothstein, Ann Fitzgerald, Katherine A. Front Immunol Immunology Detection of DNA is an important determinant of host-defense but also a driver of autoinflammatory and autoimmune diseases. Failure to degrade self-DNA in DNAseII or III(TREX1)-deficient mice results in activation of the cGAS-STING pathway. Deficiency of cGAS or STING in these models ameliorates disease manifestations. However, the contribution of the cGAS-STING pathway, relative to endosomal TLRs, in systemic lupus erythematosus (SLE) is controversial. In fact, STING deficiency failed to rescue, and actually exacerbated, disease manifestations in Fas-deficient SLE-prone mice. We have now extended these observations to a chronic model of SLE induced by the i.p. injection of TMPD (pristane). We found that both cGAS- and STING-deficiency not only failed to rescue mice from TMPD-induced SLE, but resulted in increased autoantibody production and higher proteinuria levels compared to cGAS STING sufficient mice. Further, we generated cGAS(KO)Fas(lpr) mice on a pure MRL/Fas(lpr) background using Crispr/Cas9 and found slightly exacerbated, and not attenuated, disease. We hypothesized that the cGAS-STING pathway constrains TLR activation, and thereby limits autoimmune manifestations in these two models. Consistent with this premise, mice lacking cGAS and Unc93B1 or STING and Unc93B1 developed minimal systemic autoimmunity as compared to cGAS or STING single knock out animals. Nevertheless, TMPD-driven lupus in B6 mice was abrogated upon AAV-delivery of DNAse I, implicating a DNA trigger. Overall, this study demonstrated that the cGAS-STING pathway does not promote systemic autoimmunity in murine models of SLE. These data have important implications for cGAS-STING-directed therapies being developed for the treatment of systemic autoimmunity. Frontiers Media S.A. 2021-03-29 /pmc/articles/PMC8040952/ /pubmed/33854495 http://dx.doi.org/10.3389/fimmu.2021.605930 Text en Copyright © 2021 Motwani, McGowan, Antonovitch, Gao, Jiang, Sharma, Baltus, Nickerson, Marshak-Rothstein and Fitzgerald. https://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
Motwani, Mona
McGowan, Jason
Antonovitch, Jennifer
Gao, Kevin MingJie
Jiang, Zhaozhao
Sharma, Shruti
Baltus, Gretchen A.
Nickerson, Kevin M.
Marshak-Rothstein, Ann
Fitzgerald, Katherine A.
cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE
title cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE
title_full cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE
title_fullStr cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE
title_full_unstemmed cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE
title_short cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE
title_sort cgas-sting pathway does not promote autoimmunity in murine models of sle
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040952/
https://www.ncbi.nlm.nih.gov/pubmed/33854495
http://dx.doi.org/10.3389/fimmu.2021.605930
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