DNA聚合酶β通过调控巨噬细胞焦亡抑制动脉粥样硬化发生发展的机制研究

Atherosclerosis (AS) is one of the important factors that seriously threaten human health, and the research on the mechanism of the occurrence and development of AS has important theoretical and clinical significance. In recent years, multiple studies have shown that the occurrence and development of AS are closely related to the pyroptosis, a unique form of programmed pro-inflammatory cell death. Our previous studies showed that knock down of Pol β, a key enzyme for DNA base resection and repair, pyroptosis were significantly induced in macrophages. At the same time, Polβ+/-ApoE-/- mice were more prone to AS than ApoE-/- mice. Based on this, we speculated that there may be a new mechanism for the occurrence and development of AS: inhibition of DNA damage repair protein Pol β induces macrophage pyroptosis and promotes the occurrence and development of AS. In this research, based on transgenic mice, cellular and molecular experiment, we aim to analyze whether the Pol β regulate macrophage pyroptosis through cGAS-cGAMP-STING signal pathway. Ultimately, the novel molecular mechanism of Pol β inhibiting the development and progression of atherosclerosis will be uncovered. This study will provide a new mechanism for occurrence and development of AS, and lays a theoretical foundation for the prevention and treatment of AS.

动脉粥样硬化(atherosclerosis，AS)是严重威胁人类健康的重要因素之一，研究AS发生发展的机制具有重要的理论和临床意义。近年来的研究表明，AS的发生发展与一种独特的程序性促炎性细胞死亡形式----细胞焦亡(pyroptosis)，特别是巨噬细胞焦亡密切相关。我们前期的研究发现，DNA碱基切除修复关键酶Polβ的抑制或敲除显著诱导巨噬细胞焦亡；同时，Polβ功能缺失的转基因小鼠更易产生AS表型。基于此，我们推测AS发生发展的可能存在一种新的机制：抑制DNA损伤修复蛋白Polβ诱导巨噬细胞焦亡，促进AS的发生发展。本项目将从转基因动物、细胞和分子水平，探究Polβ是否通cGAS-cGAMP-STING信号通路抑制巨噬细胞焦亡，阐明其调控巨噬细胞焦亡的分子机制，从而解密Polβ在AS发生发展中的作用，以期揭示AS发生发展的新机制，为AS的预防和治疗奠定理论基础。

类风湿性关节炎(Rheumatoid arthritis, RA)是一种慢性炎症性自身免疫性疾病，作为一种促炎性的细胞死亡形式，巨噬细胞焦亡在RA发生中至关重要， 然而，诱导巨噬细胞焦亡的具体机制仍不明确。.本研究中，我们报道了DNA聚合酶β (DNA polymerase β, Pol β)，一个关键的酶在基础切除修复，在RA发病机制中发挥了关键作用。我们的研究结果表明，在活动期的RA患者和胶原诱导的关节炎(collagen-induced arthritis, CIA)小鼠的外周血单个核细胞(peripheral blood mononuclear cells, PBMCs)中，Pol β的表达显著降低。在CIA小鼠模型中，Pol β的缺乏加剧RA的病情，病变关节巨噬细胞浸润和软骨破坏增加。 体外细胞实验表明，Pol β缺乏可加重LPS 联合 ATP诱导的巨噬细胞的焦亡，而过表达Pol β可抑制巨噬细胞的焦亡。 进一步研究发现其分子机制为，敲除Pol β可导致DNA损伤积累和胞质dsDNA泄漏，激活cGAS - STING - NF-κ b信号通路，上调NLRP3、IL-1β和IL-18的表达。. 总之，我们的研究结果阐明了Pol β对RA发生发展的影响，并为STING - NF -κB通路诱导巨噬细胞焦亡提供了新机制。