II-13 Suppression of systemic autoimmunity by the innate immune adaptor sting

<h3>Background</h3> Cytosolic DNA-sensing pathways that signal via the adaptor Stimulator of Interferon Genes (STING) mediate immunity to pathogens and have also been known to promote autoimmune pathology in DNAseII/III-deficient mice. However, the role of these pathways in systemic models of autoimmunity is unexplored. We hypothesised that cytosolic DNA sensing pathways contribute to the pathogenesis of autoimmune disease. Surprisingly, we report here that STING <i>potently</i> suppresses inflammation in several models of systemic lupus erythematosus (SLE). <h3>Materials and methods</h3> A controlled F2 intercross between heterozygote STING^± lpr^±littermates generated STING-deficient lupus-prone mice homozygous for deficiency in Fas as well as STING (STING/lpr, n<b> ≥</b>10) or wild type for STING (WT/lpr, n <b>≥</b>10). Mice were analysed at 16 wk of age. A similar F2 cross was set up for IRF3<b>⁻</b>^/<b>−</b> and MRL/lpr mice as well as STING<b>⁻</b>^/<b>−</b> and C57Bl/6^lpr/lpr and analysed as above for STING/lpr mice (n <b>≥</b>10 per group). C57BL/6, cGAS<b>⁻</b>^/<b>−</b>, Unc93b^3d/3d, and STING<b>⁻</b>^/<b>−</b> mice were injected i.p. with TMPD and evaluated at day 14 and 6 months post injection. <h3>Results</h3> Lymphoid hypertrophy, autoantibody production, serum cytokine levels, and other indicators of immune activation were markedly increased in STING<b>⁻</b>^/<b>−</b> autoimmune-prone mice compared to STING<b>⁺</b>^{/<b>+ </b>}littermates. As a result, STING<b>⁻</b>^/<b>−</b> autoimmune-prone mice had significantly shorter lifespans than controls. TLR-dependent systemic inflammation during TMPD-mediated peritonitis was similarly aggravated in STING<b>⁻</b>^{/<b>− </b>}and cGAS<b>⁻</b>^/<b>−</b> mice. Mechanistically, cGAS and STING-deficient ?macrophages failed to express negative regulators of immune activation, and thus were hyper-responsive to TLR ligands. This hyper-reactivity corresponds to dramatically elevated numbers of inflammatory macrophages and granulocytes <i>in vivo</i>. <h3>Conclusions</h3> Our findings reveal an unexpected negative regulatory role for STING during chronic inflammation. While the dysregulation of TLR7/9 signalling is a recurrent theme in systemic autoimmune, numerous studies have now revealed a <i>protective role</i> for TLR9 in SLE. Importantly, the exacerbated disease we observed in STING/lpr mice resembles that reported for TLR9/lpr mice and implies common protective mechanisms originating from STING and TLR9. Although the precise mechanism remains an open question, it is clear that cGAS/STING-dependent pathways maintain a threshold of negative regulators. We propose a similar setting of thresholds from TLR-dependent pathways and further suggest that such coordinated induction of cell-intrinsic thresholds of negative regulators is key in offsetting inflammation. Our data raise a cautionary note regarding the use of newly developed STING-directed therapeutics in systemic disease, because they may have unintended consequences and perturb a carefully orchestrated balance between cytosolic and endosomal signalling cascades.

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