title: Transient Receptor Potential Melastatin 2 (TRPM2) ion channel is required for innate immunity against Listeria monocytogenes.
abstract: 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 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 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.
authors.affiliation: Integrated Department of Immunology, National Jewish Health and University of Colorado, Denver, CO 80206, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Knowles
authors.forename: Justin W
authors.initials: JW
authors.lastname: Heizer
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Kathryn
authors.initials: K
authors.lastname: Chapman
authors.forename: Carol Anne
authors.initials: CA
authors.lastname: Ogden
authors.forename: Karl
authors.initials: K
authors.lastname: Andreasen
authors.forename: Ellen
authors.initials: E
authors.lastname: Shapland
authors.forename: Gary
authors.initials: G
authors.lastname: Kucera
authors.forename: Jennifer
authors.initials: J
authors.lastname: Mogan
authors.forename: Jessica
authors.initials: J
authors.lastname: Humann
authors.forename: Laurel L
authors.initials: LL
authors.lastname: Lenz
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Morrison
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Perraud
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D053712:Interleukin-12 Receptor beta 2 Subunit / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology* / Q000472:pathogenicity; D008088:Listeriosis / Q000276:immunology / Q000517:prevention & control; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins; D050053:TRPM Cation Channels / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000096743:Interferon gamma Receptor
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D007371:Interferon-gamma; D018664:Interleukin-12; D053712:Interleukin-12 Receptor beta 2 Subunit; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D050053:TRPM Cation Channels; D000096743:Interferon gamma Receptor; C544443:TRPM2 protein, mouse