Cytosolic double-stranded DNA (dsDNA) is a danger signal that is tightly monitored and sensed by nucleic acid-sensing pattern recognition receptors. We study the inflammatory cascade on dsDNA recognition and investigate the neuroprotective effect of cyclic GMP-AMP (cGAMP) synthase (cGAS) antagonist A151 and its mechanisms of neuroprotection in a mouse model of experimental stroke. Here, we found that cerebral ischemia promoted the release of dsDNA into the cytosol, where it initiated inflammatory responses by activating the cGAS. A151 effectively reduced the expression of cGAS, absent in melanoma 2 (AIM2) inflammasome, and pyroptosis-related molecules, including caspase-1, gasdermin D, IL-1β, and IL-18. Furthermore, mice treated with A151 showed a dampened immune response to stroke, with reduced counts of neutrophils, microglia, and microglial production of IL-6 and TNF-α after MCAO. Moreover, A151 administration significantly reduced infarct volume, attenuated neurodeficits, and diminished cell death. Notably, the protective effect of A151 was blocked in a microglia-specific cGAS knockout mouse. These findings offer unique perspectives on stroke pathogenesis and indicate that inhibition of cGAS could attenuate brain inflammatory burden, representing a potential therapeutic opportunity for stroke.

中文翻译：

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抑制双链DNA感应cGAS可改善缺血性中风后的脑损伤。

胞质双链DNA（dsDNA）是一种危险信号，由核酸传感模式识别受体密切监测和感知。我们研究了对dsDNA的炎症级联反应，并研究了环GMP-AMP（cGAMP）合酶（cGAS）拮抗剂A151的神经保护作用及其在实验性卒中小鼠模型中的神经保护机制。在这里，我们发现脑缺血促进dsDNA释放到细胞质中，并通过激活cGAS引发炎症反应。A151有效地减少了黑色素瘤2（AIM2）炎性小体中不存在的cGAS的表达，以及与凋亡相关的分子，包括caspase-1，gasdermin D，IL-1β和IL-18。此外，用A151治疗的小鼠对中风的免疫反应减弱，嗜中性粒细胞，小胶质细胞，MCAO后IL-6和TNF-α的表达和小胶质细胞的产生。此外，A151给药显着减少了梗塞体积，减轻了神经缺陷，并减少了细胞死亡。值得注意的是，A151的保护作用在小胶质细胞特异性cGAS基因敲除小鼠中被阻断。这些发现为中风的发病机理提供了独特的观点，并表明抑制cGAS可以减轻脑部炎症负担，代表中风的潜在治疗机会。