Session Title: Innate Immunity and Rheumatic Disease
Session Type: Abstract Submissions (ACR)
Background/Purpose: Innate immune sensors such as cytosolic DNA sensors and toll-like receptors (TLRs) detect viral or bacterial DNA, resulting in production of proinflammatory cytokines and type I IFNs to clear infection. Pathways involved in detecting this foreign DNA include: 1) cytosolic DNA sensors that signal through stimulator of interferon genes (STING); 2) the cytosolic sensor absent in melanoma 2 (AIM2); and 3) endosomal TLRs that traffic via Unc93. DNA derived from endogenous retroelements or dying cells have also been shown to activate these pathways, contributing to autoimmune disease. We examined the role of DNA sensor pathways in a mouse model of inflammatory arthritis in which the lysosomal endonuclease DNaseII is deficient. In this model, DNA accrual results in production of proinflammatory cytokines and type I IFNs. Since type I IFNs lead to anemia-related embryonic lethality, co-deletion of the type I IFN receptor is required (DNaseII/IFN-IR double deficient (DKO) mouse).
Methods: To investigate the contribution of DNA sensor pathways to inflammatory polyarthritis, genes involved in DNA sensor signaling were deleted on the DKO background, yielding three triple knock out (TKO) strains: STING TKO, AIM2 TKO and Unc93 TKO mice. Inflammation was assessed by clinical scoring (scale of 1-12) and by scoring of histologic inflammation in ankle joints (scale of 1-4). Anti-nuclear antibody (ANA) staining was evaluated as another marker of disease. To determine whether STING contributes to inflammation in immune-complex mediated arthritis, serum transfer arthritis (STA) was induced in STING-/- and littermate control mice.
Results: DKO mice develop significant distal polyarthritis. Clinical joint inflammation was completely absent in STING TKO mice, confirming a prior report (Ahn et al., PNAS 109:19386, 2013). However, STING deficiency did not diminish inflammation in the STA model, demonstrating that STING contributes to arthritis in the setting of DNA accrual. Clinical inflammation was significantly reduced in both AIM2 TKO and Unc93 TKO mice compared to DKO mice, demonstrating a role for the inflammasome and TLRs. Average clinical scores: DKO = 5, Het control mice = 0, STING TKO = 0, Unc93 TKO = 4, AIM2 TKO= 3.5 (p<0.05 for all strains compared to DKO). Histologic inflammation scores showed a similar pattern (DKO = 3.5, Het = 0, STING TKO = 0.5, AIM2 TKO = 2, Unc93 TKO = 3 (p<0.05 for all strains compared to DKO). The bright ANA staining pattern generated from sera of DKO mice was completely abrogated in the Unc93 TKO, but was unchanged in the STING TKO and AIM2 TKO strains.
Conclusion: These data indicate that stimulation of several innate immune sensor pathways by endogenous DNA can contribute to inflammatory polyarthritis. Although deletion of STING had the greatest impact in abrogating arthritis, the AIM2 and Unc93 pathways also contributed to joint inflammation. The TLR/Unc93 pathway, but not the STING or AIM2 pathways, mediated ANA production. These data are directly relevant to clarifying the mechanisms by which polyarthritis occurs in SLE and suggest new targets for treatment. In addition, these data demonstrate that distinct DNA sensing pathways play unique roles in disease mechanisms.
K. A. Fitzgerald,
E. M. Gravallese,
Eli Lilly and Company,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dna-sensors-regulate-inflammation-in-a-model-of-autoimmune-arthritis/