Cutting Edge: AIM2 and Endosomal TLRs Differentially Regulate Arthritis and Autoantibody Production in DNase II-Deficient Mice
Department of Medicine, Division of Rheumatology; Department of Medicine, Division of Infectious Diseases and Immunology
Immune System Diseases | Immunity | Musculoskeletal Diseases | Nucleic Acids, Nucleotides, and Nucleosides | Rheumatology
Innate immune pattern recognition receptors sense nucleic acids from microbes and orchestrate cytokine production to resolve infection. Inappropriate recognition of host nucleic acids also results in autoimmune disease. In this study, we use a model of inflammation resulting from accrual of self DNA (DNase II(-/-) type I IFN receptor [Ifnar](-/-)) to understand the role of pattern recognition receptor-sensing pathways in arthritis and autoantibody production. Using triple knockout (TKO) mice deficient in DNase II/IFNaR together with deficiency in either stimulator of IFN genes (STING) or absent in melanoma 2 (AIM2), we reveal central roles for the STING and AIM2 pathways in arthritis. AIM2 TKO mice show limited inflammasome activation and, similar to STING TKO mice, have reduced inflammation in joints. Surprisingly, autoantibody production is maintained in AIM2 and STING TKO mice, whereas DNase II(-/-) Ifnar(-/-) mice also deficient in Unc93b, a chaperone required for TLR7/9 endosomal localization, fail to produce autoantibodies to nucleic acids. Collectively, these data support distinct roles for cytosolic and endosomal nucleic acid-sensing pathways in disease manifestations.
DOI of Published Version
J Immunol. 2015 Feb 1;194(3):873-7. doi: 10.4049/jimmunol.1402573. Epub 2014 Dec 29. Link to article on publisher's site
Journal of immunology (Baltimore, Md. : 1950)
Baum R, Sharma S, Carpenter S, Li Q, Busto P, Fitzgerald KA, Marshak-Rothstein A, Gravallese EM. (2015). Cutting Edge: AIM2 and Endosomal TLRs Differentially Regulate Arthritis and Autoantibody Production in DNase II-Deficient Mice. Rheumatology Publications. https://doi.org/10.4049/jimmunol.1402573. Retrieved from https://escholarship.umassmed.edu/rheumatology_pubs/5