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

A Corrigendum to this article was published on 18 May 2012

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Abstract

The NADPH oxidase activity of phagocytes and its generation of reactive oxygen species (ROS) is critical for host defense, but ROS overproduction can also lead to inflammation and tissue injury. Here we report that TRPM2, a nonselective and redox-sensitive cation channel, inhibited ROS production in phagocytic cells and prevented endotoxin-induced lung inflammation in mice. TRPM2-deficient mice challenged with endotoxin (lipopolysaccharide) had an enhanced inflammatory response and diminished survival relative to that of wild-type mice challenged with endotoxin. TRPM2 functioned by dampening NADPH oxidase–mediated ROS production through depolarization of the plasma membrane in phagocytes. As ROS also activate TRPM2, our findings establish a negative feedback mechanism for the inactivation of ROS production through inhibition of the membrane potential–sensitive NADPH oxidase.

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Figure 1: Deletion of TRPM2 augments endotoxin-induced lung inflammation and injury.
Figure 2: Enhanced ROS generation and oxidative lung inflammatory injury after deletion of TRPM2.
Figure 3: TRPM2 has no effect on the phosphorylation of PKC-α or p47phox, and a high concentration of extracellular K+ inhibits ROS production in Trpm2−/− and Trpm2+/+ macrophages.
Figure 4: TRPM2 inhibits ROS production in macrophages through plasma membrane depolarization.
Figure 5: LPS-induced entry of Ca2+ into macrophages depends on TRPM2 expression.

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Change history

  • 03 February 2012

    In the version of this article initially published, the description of the Trpm2−/− mice in the first paragraph of the Online Methods was incomplete. That section should read as follows: "Trpm2−/− mice (obtained from B.A. Miller) were generated and originally provided by GlaxoSmithKline46. Another group has independently generated Trpm2−/− mice12; those were not used here." The new reference (46) is as follows: Knowles, H. et al. Transient receptor potential melastatin 2 (TRPM2) ion channel is required for innate immunity against Listeria monocytogenes. Proc. Natl. Acad. Sci. USA 108, 11578–11583 (2011). The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank T.E. DeCoursey, N. Demaurex, J.D. Lambeth and M.C. Dinauer for insights; B.A. Miller (Pennsylvania State University School of Medicine) for Trpm2−/− C57BL/6 mice; and G. Liu and G. Wang for technical assistance. Supported by the Francis Families Foundation (Parker B. Francis Fellowship Program, 2007−2010) and the US National Institutes of Health (P01 HL77806).

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A.D. and A.B.M. designed the study; A.D., X.-P.G., F.Q., T.K., J.H., C.H. and S.M.V. did experiments and data analysis; and A.D., R.D.Y. and A.B.M. wrote the paper.

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Correspondence to Asrar B Malik.

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The authors declare no competing financial interests.

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Di, A., Gao, XP., Qian, F. et al. The redox-sensitive cation channel TRPM2 modulates phagocyte ROS production and inflammation. Nat Immunol 13, 29–34 (2012). https://doi.org/10.1038/ni.2171

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