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Transient Receptor Potential Melastatin 2 (TRPM2) ion channel is required for innate immunity against Listeria monocytogenes

Knowles, Heather, Heizer, Justin W., Li, Yuan, Chapman, Kathryn, Ogden, Carol Anne, Andreasen, Karl, Shapland, Ellen, Kucera, Gary, Mogan, Jennifer, Humann, Jessica, Lenz, Laurel L., Morrison, Alastair D., Perraud, Anne-Laure
Proceedings of the National Academy of Sciences of the United States of America 2011 v.108 no.28 pp. 11578-11583
Listeria monocytogenes, cations, immune response, innate immunity, interleukin-12, ion channels, listeriosis, metabolites, mice, microbial growth, monocytes, pathogens, phenotype, reactive oxygen species
The generation of reactive oxygen species (ROS) is inherent to immune responses. ROS are crucially involved in host defense against pathogens by promoting bacterial killing, but also as signaling agents coordinating the production of cytokines. Transient Receptor Potential Melastatin 2 (TRPM2) is a Ca²⁺-permeable channel gated via binding of ADP-ribose, a metabolite formed under conditions of cellular exposure to ROS. Here, we show that TRPM2-deficient mice are extremely susceptible to infection with Listeria monocytogenes (Lm), exhibiting an inefficient innate immune response. In a comparison with IFNγR-deficient mice, TRPM2⁻/⁻ mice shared similar features of uncontrolled bacterial replication and reduced levels of inducible (i)NOS-expressing monocytes, but had intact IFNγ responsiveness. In contrast, we found that levels of cytokines IL-12 and IFNγ were diminished in TRPM2⁻/⁻ mice following Lm infection, which correlated with their reduced innate activation. Moreover, TRPM2⁻/⁻ mice displayed a higher degree of susceptibility than IL-12-unresponsive mice, and supplementation with recombinant IFNγ was sufficient to reverse the unrestrained bacterial growth and ultimately the lethal phenotype of Lm-infected TRPM2⁻/⁻ mice. The severity of listeriosis we observed in TRPM2⁻/⁻ mice has not been reported for any other ion channel. These findings establish an unsuspected role for ADP-ribose and ROS-mediated cation flux for innate immunity, opening up unique possibilities for immunomodulatory intervention through TRPM2.