Interleukin-22 Attenuated Renal Tubular Injury in Aristolochic Acid Nephropathy via Suppressing Activation of NLRP3 Inflammasome

Interleukin-22 Attenuated Renal Tubular Injury in Aristolochic Acid Nephropathy via Suppressing Activation of NLRP3 Inflammasome

Aristolochic acid nephropathy (AAN), as a rapidly progressive interstitial nephropathy due to excessive ingestion of aristolochia herbal medications, has recently raised considerable concerns among clinicians and researchers as its underlying pathogenic mechanisms are largely unclear. In the current study, we identified NLRP3 inflammasome activation as a novel pathological mechanism of AAN. We found that NLRP3 inflammasome was aberrantly activated both in vivo and in vitro after AA exposure. Blockade of IL-1 beta and NLRP3 inflammasome activation by IL-1Ra significantly attenuated renal tubular injury and function loss in AA-induced nephropathy. Moreover, NLRP3 or Caspase-1 deficiency protected against renal injury in the mouse model of acute AAN, suggesting that the NLRP3 signaling pathway was probably involved in the pathogenesis of AAN. We also found that administration of IL-22 could markedly attenuate renal tubular injury in AAN. Notably, IL-22 intervention significantly alleviated renal fibrosis and dysfunction in AA-induced nephropathy. Furthermore, IL-22 largely inhibited renal activation of NLRP3 inflammasome in AA-induced nephropathy. These results indicated that IL-22 ameliorated renal tubular injury in AAN through suppression of NLRP3 inflammasome activation. In summary, this study identified renal activation of NLRP3 inflammasome as a novel mechanism underlying the pathogenesis of AAN, thus providing a potential therapeutic strategy for AAN based on suppression of NLRP3 inflammasome activation.

马兜铃酸肾病（AAN）是一种因过量摄入含马兜铃属草药的药物而导致的快速进展性间质性肾病，由于其潜在的致病机制在很大程度上尚不明确，最近在临床医生和研究人员中引起了相当大的关注。在本研究中，我们确定NLRP3炎症小体激活是AAN的一种新的病理机制。我们发现，在马兜铃酸（AA）暴露后，NLRP3炎症小体在体内和体外均异常激活。通过白细胞介素 - 1受体拮抗剂（IL - 1Ra）阻断白细胞介素 - 1β（IL - 1β）和NLRP3炎症小体的激活，可显著减轻AA诱导的肾病中的肾小管损伤和功能丧失。此外，在急性AAN小鼠模型中，NLRP3或半胱天冬酶 - 1（Caspase - 1）缺陷可防止肾损伤，这表明NLRP3信号通路可能参与了AAN的发病机制。我们还发现，给予白细胞介素 - 22（IL - 22）可显著减轻AAN中的肾小管损伤。值得注意的是，IL - 22干预可显著缓解AA诱导的肾病中的肾纤维化和功能障碍。此外，在AA诱导的肾病中，IL - 22在很大程度上抑制了NLRP3炎症小体在肾脏的激活。这些结果表明，IL - 22通过抑制NLRP3炎症小体的激活来改善AAN中的肾小管损伤。总之，本研究确定肾脏中NLRP3炎症小体的激活是AAN发病机制的一种新机制，从而为基于抑制NLRP3炎症小体激活的AAN治疗提供了一种潜在的策略。