Department of Anesthesiology, Washington University School of Medicine in St Louis, St. Louis, Missouri, USA.
Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine in St Louis, St Louis, Missouri, USA.
Ann Rheum Dis. 2021 Dec;80(12):1604-1614. doi: 10.1136/annrheumdis-2021-220295. Epub 2021 Oct 18.
Crystal structures activate innate immune cells, especially macrophages and initiate inflammatory responses. We aimed to understand the role of the mechanosensitive TRPV4 channel in crystal-induced inflammation. Real-time RT-PCR, RNAscope in situ hybridisation, and mice were used to examine TRPV4 expression and whole-cell patch-clamp recording and live-cell Ca imaging were used to study TRPV4 function in mouse synovial macrophages and human peripheral blood mononuclear cells (PBMCs). Both genetic deletion and pharmacological inhibition approaches were used to investigate the role of TRPV4 in NLRP3 inflammasome activation induced by diverse crystals in vitro and in mouse models of crystal-induced pain and inflammation in vivo. TRPV4 was functionally expressed by synovial macrophages and human PBMCs and TRPV4 expression was upregulated by stimulation with monosodium urate (MSU) crystals and in human PBMCs from patients with acute gout flares. MSU crystal-induced gouty arthritis were significantly reduced by either genetic ablation or pharmacological inhibition of TRPV4 function. Mechanistically, TRPV4 mediated the activation of NLRP3 inflammasome by diverse crystalline materials but not non-crystalline NLRP3 inflammasome activators, driving the production of inflammatory cytokine interleukin-1β which elicited TRPV4-dependent inflammatory responses in vivo. Moreover, chemical ablation of the TRPV1-expressing nociceptors significantly attenuated the MSU crystal-induced gouty arthritis. In conclusion, TRPV4 is a common mediator of inflammatory responses induced by diverse crystals through NLRP3 inflammasome activation in macrophages. TRPV4-expressing resident macrophages are critically involved in MSU crystal-induced gouty arthritis. A neuroimmune interaction between the TRPV1-expressing nociceptors and the TRPV4-expressing synovial macrophages contributes to the generation of acute gout flares.
晶体结构激活先天免疫细胞，特别是巨噬细胞，并引发炎症反应。我们旨在了解机械敏感 TRPV4 通道在晶体诱导的炎症中的作用。使用实时 RT-PCR、RNAscope 原位杂交和小鼠来检查 TRPV4 表达，使用全细胞膜片钳记录和活细胞 Ca2+成像来研究 TRPV4 在小鼠滑膜巨噬细胞和人外周血单核细胞 (PBMC) 中的功能。使用基因缺失和药理学抑制方法研究 TRPV4 在不同晶体体外诱导 NLRP3 炎性体激活以及在体内晶体诱导疼痛和炎症模型中的作用。TRPV4 由滑膜巨噬细胞和人 PBMC 功能性表达，刺激尿酸单钠 (MSU) 晶体和急性痛风发作患者的人 PBMC 中 TRPV4 表达上调。TRPV4 功能缺失或药理学抑制均可显著减轻 MSU 晶体诱导的痛风性关节炎。从机制上讲，TRPV4 介导多种晶体材料激活 NLRP3 炎性体，但不介导非晶体 NLRP3 炎性体激活剂，从而驱动炎症细胞因子白细胞介素-1β的产生，在体内引发 TRPV4 依赖性炎症反应。此外，TRPV1 表达的伤害感受器的化学消融显著减轻了 MSU 晶体诱导的痛风性关节炎。总之，TRPV4 是通过巨噬细胞中 NLRP3 炎性体激活引起多种晶体诱导的炎症反应的共同介质。表达 TRPV4 的固有巨噬细胞在 MSU 晶体诱导的痛风性关节炎中起着关键作用。TRPV1 表达的伤害感受器和表达 TRPV4 的滑膜巨噬细胞之间的神经免疫相互作用有助于急性痛风发作的产生。
