Transient receptor potential melastatin 2 regulates neutrophil extracellular traps formation and delays resolution of neutrophil-driven sterile inflammation
Xue Cao, Yanhong Li, Yubin Luo, Tianshu Chu, Hang Yang, Wen Ji, Yi Liu, Yi Zhao, Martin Herrmann
Abstract
Abstract The formation of neutrophil extracellular traps (NETs) is a process releasing into the extracellular space networks of chromatin fibers decorated with granular proteins. It is implicated in infection-related as well as sterile inflammation. Monosodium urate (MSU) crystals serve as damage-associated molecular pattern (DAMP) in various conditions of disease. Formation of NETs or aggregated NETs (aggNETs) orchestrates initiation and resolution of MSU crystals-triggered inflammation, respectively. Elevated intracellular calcium levels and the generation of reactive oxygen species (ROS) are crucial for the formation of MSU crystal-induced NETs. However, the exact signaling pathways involved are still elusive. Herein, we demonstrate that the ROS-sensing, non-selective calcium-permeable channel transient receptor potential cation channel subfamily M member 2 (TRPM2) is required for a full-blown MSU crystal-induced NET formation. Primary neutrophils from TRPM2 −/− mice showed reduced calcium influx and ROS production and, consequently a reduced formation of MSU crystal-induced NETs and aggNETs. Furthermore, in TRPM2 −/− mice the infiltration of inflammatory cells into infected tissues and their production of inflammatory mediators was suppressed. Taken together these results describe an inflammatory role of TRPM2 for neutrophil-driven inflammation and identify TRPM2 as potential target for therapeutic intervention.