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

摘要

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. Tran sient Receptor Potential Melastatin 2 (TRPM2) is a Ca～(2+)-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 re sponse. In a comparison with IFNγR-deficient mice, TRPM2-/- mice shared similar features of uncontrolled bacterial replication and re duced levels of inducible (i)NOS-expressing monocytes, but had in tact IFNγ responsiveness. In contrast, we found that levels of cytokines IL-12 and IFNγ were diminished in TRPM2 ～(-/-)mice follow ing Lm infection, which correlated with their reduced innate activa tion. 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.