dsDNA-induced AIM2 pyroptosis halts aberrant inflammation during rhabdomyolysis-induced acute kidney injury
dsDNA-induced AIM2 pyroptosis halts aberrant inflammation during rhabdomyolysis-induced acute kidney injury
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DOI：
10.1038/s41418-022-01033-9
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发表时间：
2022-06-23
影响因子：
12.4
通讯作者：
Takahashi, Masafumi
中科院分区：
文献类型：
--
作者：
Baatarjav, Chintogtokh;Komada, Takanori;Takahashi, Masafumi
横纹肌溶解症是一种严重的疾病，通常会导致急性肾损伤（阿基）。虽然从损伤肌肉释放的双链DNA（dsDNA）可能参与其发病机制，但dsDNA如何促进横纹肌溶解诱导的阿基（RIAKI）的确切机制仍然不清楚。在黑素瘤2（AIM 2）中不存在的dsDNA传感器形成炎性小体并诱导gasdermin D（GSDMD）裂解，导致称为焦亡的炎性细胞死亡。在这项使用RIAKI小鼠模型的研究中，我们发现Aim 2缺乏导致大量巨噬细胞积聚，导致功能恢复延迟和肾脏纤维化持续。虽然Aim 2缺陷损害RIAKI诱导的肾巨噬细胞焦亡，但它意外地加速了异常炎症，如CXCR 3（+）CD 206（+）巨噬细胞积聚和TBK 1-IRF 3/NF-κ B活化所证明的。具有完整AIM 2的肾脏巨噬细胞在dsDNA的作用下发生迅速的细胞热凋亡，而没有释放IL-1 β。另一方面，dsDNA诱导的Aim 2缺陷型巨噬细胞从快速的热凋亡消除中逃脱，而是参与STING-TBK 1-IRF 3/NF-κ B信号传导，导致炎症表型恶化。总的来说，这些发现揭示了迄今为止未知的免疫调节功能的巨噬细胞pyroptosis。dsDNA诱导的快速巨噬细胞死亡可能作为抗炎程序并决定RIAKI的愈合过程。
Rhabdomyolysis is a severe condition that commonly leads to acute kidney injury (AKI). While double-stranded DNA (dsDNA) released from injured muscle can be involved in its pathogenesis, the exact mechanism of how dsDNA contributes to rhabdomyolysis-induced AKI (RIAKI) remains obscure. A dsDNA sensor, absent in melanoma 2 (AIM2), forms an inflammasome and induces gasdermin D (GSDMD) cleavage resulting in inflammatory cell death known as pyroptosis. In this study using a mouse model of RIAKI, we found that Aim2-deficiency led to massive macrophage accumulation resulting in delayed functional recovery and perpetuating fibrosis in the kidney. While Aim2-deficiency compromised RIAKI-induced kidney macrophage pyroptosis, it unexpectedly accelerated aberrant inflammation as demonstrated by CXCR3(+)CD206(+) macrophage accumulation and activation of TBK1-IRF3/NF-kappa B. Kidney macrophages with intact AIM2 underwent swift pyroptosis without IL-1 beta release in response to dsDNA. On the other hand, dsDNA-induced Aim2-deficient macrophages escaped from swift pyroptotic elimination and instead engaged STING-TBK1-IRF3/NF-kappa B signalling, leading to aggravated inflammatory phenotypes. Collectively, these findings shed light on a hitherto unknown immunoregulatory function of macrophage pyroptosis. dsDNA-induced rapid macrophage cell death potentially serves as an anti-inflammatory program and determines the healing process of RIAKI.