Serum apolipoprotein C3 (APOC3) predicts incident cardiovascular events in people with type 1 diabetes and silencing of APOC3 prevents both lesion initiation and advanced lesion necrotic core expansion in a mouse model of type 1 diabetes. APOC3 acts by slowing the clearance of triglyceride-rich lipoproteins, but lipid-free APOC3 has recently been reported to activate an inflammasome pathway in monocytes. We therefore investigated the contribution of hematopoietic inflammasome pathways to atherosclerosis in mouse models of type 1 diabetes. LDL receptor-deficient diabetes mouse models were transplanted with bone marrow from donors deficient in NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), absent in melanoma 2 (AIM2), or gasdermin D (GSDMD), an inflammasome-induced executor of pyroptotic cell death. Mice with diabetes exhibited inflammasome activation, and consistently, increased plasma interleukin-1β (IL-1β) and IL-18. Hematopoietic deletions of NLRP3, AIM2 or GSDMD caused smaller atherosclerotic lesions in diabetic mice. The increased lesion necrotic core size in diabetic mice was independent of macrophage pyroptosis because hematopoietic GSDMD-deficiency failed to prevent necrotic core expansion in advanced lesions. Our findings demonstrate that AIM2 and NLRP3 inflammasomes contribute to atherogenesis in diabetes and suggest that necrotic core expansion is independent of macrophage pyroptosis.

中文翻译：

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造血 NLRP3 和 AIM2 炎症小体促进糖尿病加速的动脉粥样硬化，但坏死的增加与细胞焦亡无关

血清载脂蛋白 C3 (APOC3) 可预测 1 型糖尿病患者的心血管事件，而 APOC3 的沉默可防止 1 型糖尿病小鼠模型中的病变起始和晚期病变坏死核心扩张。APOC3 的作用是减缓富含甘油三酯的脂蛋白的清除，但最近有报道称无脂质的 APOC3 可激活单核细胞中的炎症通路。因此，我们研究了造血炎性体通路对 1 型糖尿病小鼠模型中动脉粥样硬化的作用。LDL 受体缺陷型糖尿病小鼠模型移植了来自 NOD-、LRR- 和含吡啶结构域蛋白 3 (NLRP3) 缺陷的供体的骨髓，黑色素瘤 2 (AIM2) 或 gasdermin D (GSDMD) 中缺乏，一种炎性小体-诱导细胞焦亡的执行者。患有糖尿病的小鼠表现出炎症小体激活，并持续增加血浆白细胞介素-1β (IL-1β) 和 IL-18。NLRP3、AIM2 或 GS​​DMD 的造血缺失导致糖尿病小鼠的动脉粥样硬化病变较小。糖尿病小鼠病变坏死核心大小的增加与巨噬细胞焦亡无关，因为造血 GSDMD 缺陷未能阻止晚期病变的坏死核心扩张。我们的研究结果表明，AIM2 和 NLRP3 炎症小体有助于糖尿病的动脉粥样硬化形成，并表明坏死核心扩张与巨噬细胞焦亡无关。糖尿病小鼠病变坏死核心大小的增加与巨噬细胞焦亡无关，因为造血 GSDMD 缺陷未能阻止晚期病变的坏死核心扩张。我们的研究结果表明，AIM2 和 NLRP3 炎症小体有助于糖尿病的动脉粥样硬化形成，并表明坏死核心扩张与巨噬细胞焦亡无关。糖尿病小鼠病变坏死核心大小的增加与巨噬细胞焦亡无关，因为造血 GSDMD 缺陷未能阻止晚期病变的坏死核心扩张。我们的研究结果表明，AIM2 和 NLRP3 炎症小体有助于糖尿病的动脉粥样硬化形成，并表明坏死核心扩张与巨噬细胞焦亡无关。