AIM2 and endosomal TLRs differentially regulate arthritis and autoantibody production in DNase II deficient mice. Mus musculus

Innate immune PRRs sense nucleic acids from microbes and orchestrate cytokine production to resolve infection. Inappropriate recognition of host nucleic acids also results in autoimmune disease. Here we utilize a model of inflammation resulting from accrual of self DNA (DNase II-/- Ifnar-/-) to understand the role of PRR sensing pathways in arthritis and autoantibody production. Using mice deficient in DNase II/Ifnar together with deficiency in either STING or AIM2 (TKO), we reveal central roles for the STING and AIM2 pathway in arthritis. AIM2 TKO mice show limited inflammasome activation and, like STING TKO mice, have reduced inflammation in joints. Surprisingly, autoantibody production is maintained in AIM2 and STING TKO mice, while 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. Overall design: Sera from 3 month-old DKO and STING TKO mice were used (2 samples/genotype) as well as sera from 10 month-old DKO (3 samples), STING TKO (5 samples), AIM2 TKO (4 samples), and Unc93b TKO (3 samples)