Zhao Li, Zhao Tianyi, Yang Xue, Cao Ling, Xu Rui, Liu Jiyu, Lin Cong, Yu Yiyun, Xuan Dandan, Zhu Xiaoxia, Liu Lei, Hua Yinghui, Deng Chunhui, Wan Weiguo, Zou Hejian, Xue Yu
Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai.
Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Zhejiang.
Rheumatology (Oxford). 2022 Aug 30;61(9):3841-3853. doi: 10.1093/rheumatology/keac009.
Interleukin (IL)-37 is a natural suppressor of inflammation. Macrophages play an important role in acute gout flare by dominating the inflammation and spontaneous relief. We have reported that IL-37 could limit runaway inflammation in gout. Here we focus on whether IL-37 inhibits gouty inflammation by altering macrophage functions, and how it does so.
Macrophage functions were evaluated in terms of phagocytosis, pyroptosis, polarization and metabolism. Phagocytosis and polarization of macrophages were detected by side scattering and double-labelling induced nitrogen monoxide synthase (iNOS)/arginase-1 (Arg-1) using flow cytometry, respectively. Transcription of pyroptosis-related molecules was detected by qPCR. Metabolomics was performed by liquid chromatograph mass spectrometer. Human IL-37 knock-in mice and a model with point mutation (S9A) at mouse Gsk3b locus were created by CRISPR/Cas-mediated genome engineering. MSU was injected into the paws and peritoneal cavity to model acute gout. Vernier calliper was used to measure the thickness of the paws. The mice paws and human synovium tissues or tophi were collected for pathological staining. Peritoneal fluid of mice was used to enrich macrophages to detect polarization.
IL-37 promoted non-inflammatory phagocytic activity of macrophages by enhancing phagocytosis of MSU, reducing transcription of pyroptosis-related proteins and release of inflammatory cytokines, protecting mitochondrial function, and mediating metabolic reprogramming in MSU-treated THP-1 cells. These multifaceted roles of IL-37 were partly depended on the mediation of glycogen synthase kinase-3β (GSK-3β).
Our study revealed that IL-37 could shape macrophages into a 'silent' non-inflammatory phagocytic fashion. IL-37 may become a potentially valuable treatment option for patients of chronic gout, especially for those with tophi.
白细胞介素（IL）-37是一种天然的炎症抑制因子。巨噬细胞在急性痛风发作中通过主导炎症和自然缓解发挥重要作用。我们曾报道IL-37可限制痛风中的失控性炎症。在此，我们聚焦于IL-37是否通过改变巨噬细胞功能来抑制痛风性炎症以及其具体机制。
从吞噬作用、焦亡、极化和代谢方面评估巨噬细胞功能。分别通过侧向散射和使用流式细胞术双标记诱导型一氧化氮合酶（iNOS）/精氨酸酶-1（Arg-1）检测巨噬细胞的吞噬作用和极化。通过qPCR检测焦亡相关分子的转录。采用液相色谱质谱仪进行代谢组学分析。通过CRISPR/Cas介导的基因组工程创建人IL-37基因敲入小鼠和小鼠Gsk3b基因座点突变（S9A）模型。将单钠尿酸盐（MSU）注射到爪部和腹腔以模拟急性痛风。使用游标卡尺测量爪部厚度。收集小鼠爪部和人滑膜组织或痛风石进行病理染色。使用小鼠腹腔液富集巨噬细胞以检测极化。
IL-37通过增强MSU的吞噬作用、减少焦亡相关蛋白的转录和炎性细胞因子的释放、保护线粒体功能以及介导MSU处理的THP-1细胞中的代谢重编程，促进巨噬细胞的非炎性吞噬活性。IL-37的这些多方面作用部分依赖于糖原合酶激酶-3β（GSK-3β）的介导。
我们的研究表明，IL-37可使巨噬细胞形成“沉默”的非炎性吞噬方式。IL-37可能成为慢性痛风患者，尤其是有痛风石患者潜在的有价值的治疗选择。
