Liu Chongbin, Shen Yanting, Huang Liuwei, Wang Jun
Clinical Research Center of Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
Department of Nephrology, The First People's Hospital of Kashi, Kashi, PR China.
Cell Death Discov. 2022 Apr 26;8(1):232. doi: 10.1038/s41420-022-01032-2.
Acute kidney injury (AKI) is characterized by necroinflammation formed by necrotic tubular epithelial cells (TECs) and interstitial inflammation. In necroinflammation, macrophages are key inflammatory cells and can be activated and polarized into proinflammatory macrophages. Membranous Toll-like receptors (TLRs) can cooperate with intracellular NOD-like receptor protein 3 (NLRP3) to recognize danger signals from necrotic TECs and activate proinflammatory macrophages by assembling NLRP3 inflammasome. However, the cooperation between TLRs and NLRP3 is still unclear. Using conditioned medium from necrotic TECs, we confirmed that necrotic TECs could release danger signals to activate NLRP3 inflammasome in macrophages. We further identified that necrotic TECs-induced NLRP3 inflammasome activation was dependent on ATP secretion via Pannexin-1 (Panx1) channel in macrophages. Next, we verified that TLR2 was required for the activation of Panx1 and NLRP3 in macrophages. Mechanistically, we indicated that caspase-5 mediated TLR2-induced Panx1 activation. In addition, we showed that necrotic TECs-induced activation of TLR2/caspase-5/Panx1 axis could be decreased in macrophages when TECs was protected by N-acetylcysteine (NAC). Overall, we demonstrate that danger signals from necrotic TECs could activate NLRP3 inflammasome in macrophages via TLR2/caspase-5/Panx1 axis during AKI.
急性肾损伤（AKI）的特征是由坏死的肾小管上皮细胞（TECs）形成的坏死性炎症和间质炎症。在坏死性炎症中，巨噬细胞是关键的炎症细胞，可被激活并极化为促炎性巨噬细胞。膜型Toll样受体（TLRs）可与细胞内NOD样受体蛋白3（NLRP3）协同作用，识别来自坏死TECs的危险信号，并通过组装NLRP3炎性小体激活促炎性巨噬细胞。然而，TLRs与NLRP3之间的协同作用仍不清楚。利用坏死TECs的条件培养基，我们证实坏死TECs可释放危险信号以激活巨噬细胞中的NLRP3炎性小体。我们进一步确定，坏死TECs诱导的NLRP3炎性小体激活依赖于巨噬细胞中通过泛连接蛋白-1（Panx1）通道分泌的ATP。接下来，我们验证了TLR2是巨噬细胞中Panx1和NLRP3激活所必需的。从机制上讲，我们表明半胱天冬酶-5介导TLR2诱导的Panx1激活。此外，我们还表明，当TECs受到N-乙酰半胱氨酸（NAC）保护时，坏死TECs诱导的巨噬细胞中TLR2/半胱天冬酶-5/Panx1轴的激活会降低。总体而言，我们证明在AKI期间，来自坏死TECs的危险信号可通过TLR2/半胱天冬酶-5/Panx1轴激活巨噬细胞中的NLRP3炎性小体。
