II-13 Suppression of systemic autoimmunity by the innate immune adaptor sting
Bibliographic record
Abstract
Background 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 potently suppresses inflammation in several models of systemic lupus erythematosus (SLE).Materials and methods 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 ≥10) or wild type for STING (WT/lpr, n ≥10). Mice were analysed at 16 wk of age. A similar F2 cross was set up for IRF3−/− and MRL/lpr mice as well as STING−/− and C57Bl/6lpr/lpr and analysed as above for STING/lpr mice (n ≥10 per group). C57BL/6, cGAS−/− , Unc93b3d/3d, and STING−/− mice were injected i.p. with TMPD and evaluated at day 14 and 6 months post injection.Results Lymphoid hypertrophy, autoantibody production, serum cytokine levels, and other indicators of immune activation were markedly increased in STING −/− autoimmune-prone mice compared to STING+/+ littermates. As a result, STING−/− autoimmune-prone mice had significantly shorter lifespans than controls. TLR-dependent systemic inflammation during TMPD-mediated peritonitis was similarly aggravated in STING−/− and cGAS−/− 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 in vivo.Conclusions 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 protective role 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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".