UMMS Affiliation

Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine; Division of Rheumatology, Department of Medicine

Publication Date

2021-03-29

Document Type

Article

Disciplines

Immune System Diseases | Immunity

Abstract

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.

Keywords

DNaseI, SLE, TLRs, cGAS/STING, pristane

Rights and Permissions

Copyright © 2021 Motwani, McGowan, Antonovitch, Gao, Jiang, Sharma, Baltus, Nickerson, Marshak-Rothstein and Fitzgerald. 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.

DOI of Published Version

10.3389/fimmu.2021.605930

Source

Motwani M, McGowan J, Antonovitch J, Gao KM, Jiang Z, Sharma S, Baltus GA, Nickerson KM, Marshak-Rothstein A, Fitzgerald KA. cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE. Front Immunol. 2021 Mar 29;12:605930. doi: 10.3389/fimmu.2021.605930. PMID: 33854495; PMCID: PMC8040952. Link to article on publisher's site

Journal/Book/Conference Title

Frontiers in immunology

Related Resources

Link to Article in PubMed

PubMed ID

33854495

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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