The redox-sensitive cation channel TRPM2 modulates phagocyte ROS production and inflammation

Anke Di,et al. Nature immunology 13, 29–34 (2012)

Speaker: Yin-Chiou, Luo (羅尹秋)                               Time:14:00~15:00, Mat. 7, 2011

Commentator: Pei-Jane Tsai, Ph.D. (蔡佩珍老師)       Place: Room 601

Abstract

Reactive oxygen species (ROS) is critical for antimicrobial systems, but ROS overproduction also causes inflammation and extensive tissue damage. NADPH oxidases are the major sources of ROS, and many mechanisms activate NADPH oxidases, including the plasma membrane potential and activation of protein kinase C-α. TRPM2 (transient receptor potential melastatin 2) is a Ca²⁺ and Na⁺-permeablecation channel activated by intracellular messengers such as Ca²⁺, H₂O₂ and ADPR. Previous study indicated that in the DSS-induced model of colitis, Trpm2-knockout mice showed attenuation of inflammatory response (1). Therefore the authors surmised that TRPM2 activated NADPH oxidases through the activation of Ca²⁺-dependent PKC-α. However, contrary to results obtained for DSS-induced colitis inflammation, the authors revealed that Trpm2-/- miceaugmented endotoxin-induced lung inflammation and injury. In addition, they observed that deletion of TRPM2 enhanced ROS generation. The authors next investigated the mechanism of TRPM2 inhibited ROS production. They measured ROS production at various membrane potentials, and tested whether TRPM2 regulates ROS production by altering the membrane potential. They found that TRPM2 inhibited ROS production through plasma membrane depolarization. Furthermore, the authors determined whether deletion of TRPM2 lead to enhancedCa²⁺signaling induced by other Ca²⁺channel. They added PAF (platelet activating factor) to change intracellular Ca²⁺ concentration, and found that deletion of TRPM2 did not  increase intracellular Ca²⁺ concentration induced by PAF. Thus, deletion of TRPM2 was not compensated for changing in the activation of otherCa²⁺channel. This study provides evidence for TRPM2 acting as an essential modulator of plasma membrane potential by conducting the influx of cations, and preventing NADPH oxidase-derived ROS production.

References:

1. Yamamoto, S. et al. TRPM2-mediatedCa²⁺ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nat. Med.14, 738-747 (2008)