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The TRPM2 ion channel, an oxidative stress and metabolic sensor regulating innate immunity and inflammation

  • Immunology in Colorado
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Abstract

TRPM2 (transient receptor potential melastatin 2) is the unique fusion of a Ca2+-permeable pore with an enzymatic domain that binds the NAD+-metabolite ADP-ribose (ADPR), resulting in channel opening. ADPR formation is a metabolic corollary of cellular stress, but can also be elicited enzymatically through NAD glycohydrolases like CD38. TRPM2 thus functions as a metabolic and oxidative stress sensor and translates this information into ion fluxes that can affect Ca2+ signaling and the membrane potential. TRPM2 is strongly represented in immune cells of the phagocytic lineage, themselves professional generators of oxidants. The recent characterization of TRPM2-deficient mouse models has revealed the involvement of this channel in various aspects of immunity. Monocytes lacking TRPM2 show reduced production of the CXCL2 chemokine, resulting in diminished neutrophilic influx to the colon in chemically induced colitis, and thus protection against tissue ulceration in TRPM2−/− mice. However, the insufficient production of proinflammatory cytokines leads to high morbidity and lethality of the TRPM2−/− mice following infection with the bacterial pathogen Listeria monocytogenes. In the context of endotoxin-induced pulmonary inflammation, TRPM2’s absence was found to promote inflammation and ROS production. TRPM2 acts thereby as a negative feedback loop by interfering through membrane depolarization with ROS generation by NADPH oxidases. In dendritic cells, TRPM2 is a lysosomal Ca2+-release channel that promotes chemokine responsiveness and cell migration, which is reminiscent of CD38-mediated functions. The discovery of TRPM2 has unveiled an unsuspected signaling pathway and established ADPR as a novel second messenger. Understanding TRPM2’s complex involvement in inflammation is crucial to evaluating the potential of manipulating TRPM2 activity and ADPR metabolism for therapeutic intervention.

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Acknowledgments

Support by an Early Excellence Award of the Sandler Program in Asthma Research (A.-L. P.), by NIH grant R01GM068801 (A. -L. P.), and by NIH training grant #5 T32 AI07405 (H. K.), is acknowledged. We would also like to thank Carsten Schmitz (UC Denver & National Jewish Health) for carefully reviewing the manuscript. The authors declare no conflict of interest.

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  1. Integrated Department of Immunology, National Jewish Health and University of Colorado Denver School of Medicine, 1400 Jackson St, Denver, CO, 80206, USA

    Heather Knowles, Yuan Li & Anne-Laure Perraud

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  1. Heather Knowles
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  2. Yuan Li
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Correspondence to Anne-Laure Perraud.

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Knowles, H., Li, Y. & Perraud, AL. The TRPM2 ion channel, an oxidative stress and metabolic sensor regulating innate immunity and inflammation. Immunol Res 55, 241–248 (2013). https://doi.org/10.1007/s12026-012-8373-8

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