Summary The presence of DNA in the cytoplasm is normally a sign of microbial infections and is quickly detected by cyclic GMP-AMP synthase (cGAS) to elicit anti-infection immune responses. However, chronic activation of cGAS by self-DNA leads to severe autoimmune diseases for which no effective treatment is available yet. Here we report that acetylation inhibits cGAS activation and that the enforced acetylation of cGAS by aspirin robustly suppresses self-DNA-induced autoimmunity. We find that cGAS acetylation on either Lys384, Lys394, or Lys414 contributes to keeping cGAS inactive. cGAS is deacetylated in response to DNA challenges. Importantly, we show that aspirin can directly acetylate cGAS and efficiently inhibit cGAS-mediated immune responses. Finally, we demonstrate that aspirin can effectively suppress self-DNA-induced autoimmunity in Aicardi-Goutières syndrome (AGS) patient cells and in an AGS mouse model. Thus, our study reveals that acetylation contributes to cGAS activity regulation and provides a potential therapy for treating DNA-mediated autoimmune diseases.
Neuropsychiatric systemic lupus erythematosus (NPSLE) represents a significant and growing challenge in both clinical practice and research, with its mechanistic investigation hindered by the lack of reliable animal models. Over the past two decades, we have established that immunogenic self-DNA can induce SLE disease model, which has been widely utilized in the academic community. To modify the doses of immunogenic self-DNA, validate the induction of SLE disease, and systematically characterize the resulting neuropsychiatric manifestations, aiming to provide an optimal model for NPSLE. Conventional genetic background BALB/c mice were immunized with 75 µg of immunogenic self-DNA. Based on the criteria and diagnostic recommendations from the ACR and EULAR, we conducted neurobehavioral experiments to assess the neuropsychiatric manifestations of clinical NPSLE patients. Whole-cell patch-clamp electrophysiological recordings were performed on mouse brain slices to assess electroencephalographic (EEG) abnormalities associated with NPSLE. Cerebrospinal fluid (CSF) abnormalities were evaluated by measuring inflammatory factors in the CSF. Additionally, histopathological analyses were conducted to evaluate MRI abnormalities in self-DNA immunized mice. Self-DNA immunized mice developed progressive cognitive impairments, exhibiting spatial and working memory deficits from week 8 post-immunization, which worsened by week 12, alongside the emergence of anxiety-like and depression-like behaviors. In parallel, electrophysiological analysis revealed synaptic transmission deficits and reduced neuronal excitability beginning at week 8, further deteriorating by week 12. Of note, blood-brain barrier (BBB) disruption was observed at 4–8 weeks post immunization, which was evidenced by IgG leakage and FITC-dextran extravasation. Such BBB disruption was accompanied by elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-10), resembling neuropsychiatric lupus pathology. Finally, histologically, hippocampal neuronal loss and dendritic spine reduction in CA1, CA3, and DG subregions were observed, providing structural correlates for the observed memory deficits in self-DNA immunized mice. This model induced by immunogenic self-DNA recapitulated the neurological manifestations observed in clinical patients, rendering it a robust model for the research of NPSLE.
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