Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Sciences, Shandong University, Jinan, People's Republic of China.
Department of Pathogenic Biology, School of Basic Medicine Sciences, Shandong University, Jinan, People's Republic of China.
Inflamm Bowel Dis. 2021 Jan 1;27(1):84-93. doi: 10.1093/ibd/izaa124.
Interleukin-37 (IL-37) is a new negative immune regulator. It has 5 splicing forms, IL-37a-e, and most research mainly focuses on IL-37b functions in diverse diseases. Our previous research found that IL-37d inhibits lipopolysaccharide-induced inflammation in endotoxemia through a mechanism different from that of IL-37b. However, whether IL-37d plays a role in colitis and the underlying mechanisms is still obscure. Herein, we identified whether IL-37d regulates NLRP3 inflammasome activity and determined its effect on colitis.
NLRP3 inflammasome in macrophages from IL-37d transgenic (IL-37dtg) and control wild type (WT) mice were activated by lipopolysaccharide and adenosine 5'-triphosphate. The expression of NLRP3 inflammasome components and its downstream effector, IL-1β, were detected by real-time polymerase chain reaction, western blot, and ELISA. The models of alum-induced peritonitis and dextran sodium sulfate (DSS)-induced colitis were used to investigate the function of IL-37d on regulating the activity of NLRP3 inflammasome in vivo.
Our results showed that the activation of NLRP3 inflammasome in macrophage and alum-induced peritonitis was inhibited by IL-37d. Strikingly, IL-37d suppressed NLRP3 expression at the priming step via inhibiting NF-κB activation by transcriptional profiling. Moreover, the recombinant protein IL-37d attenuated NLRP3 inflammasome activation and the production of IL-1β, which could be reversed by IL-1R8 knockdown. Finally, IL-37d transgenic mice resisted DSS-induced acute colitis and NLRP3 inflammasome activation.
Interleukin-37d inhibits overactivation of the NLRP3 inflammasome through regulating NLRP3 transcription in an IL-1R8 receptor-mediated signaling pathway.
白细胞介素-37（IL-37）是一种新的负免疫调节剂。它有 5 种剪接形式，IL-37a-e，大多数研究主要集中在 IL-37b 在各种疾病中的功能。我们之前的研究发现，IL-37d 通过与 IL-37b 不同的机制抑制内毒素血症中的脂多糖诱导的炎症。然而，IL-37d 是否在结肠炎中发挥作用及其潜在机制仍不清楚。在此，我们确定了 IL-37d 是否调节 NLRP3 炎性体活性，并确定了其对结肠炎的影响。
用脂多糖和三磷酸腺苷激活来自 IL-37d 转基因（IL-37dtg）和对照野生型（WT）小鼠的巨噬细胞中的 NLRP3 炎性体。通过实时聚合酶链反应、western blot 和 ELISA 检测 NLRP3 炎性体成分及其下游效应物 IL-1β的表达。使用明矾诱导的腹膜炎和葡聚糖硫酸钠（DSS）诱导的结肠炎模型研究 IL-37d 对体内 NLRP3 炎性体活性的调节作用。
我们的结果表明，IL-37d 抑制了巨噬细胞中 NLRP3 炎性体的激活和明矾诱导的腹膜炎。引人注目的是，通过转录谱分析，IL-37d 通过抑制 NF-κB 激活来抑制 NLRP3 的初始激活。此外，重组蛋白 IL-37d 减弱了 NLRP3 炎性体的激活和 IL-1β的产生，这可以通过 IL-1R8 敲低来逆转。最后，IL-37d 转基因小鼠抵抗 DSS 诱导的急性结肠炎和 NLRP3 炎性体激活。
白细胞介素-37 通过在 IL-1R8 受体介导的信号通路中调节 NLRP3 转录来抑制 NLRP3 炎性体的过度激活。
