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Published on: March 17, 2015
Transient Receptor Potential Melastatin 2 (TRPM2) ion channel is required for innate immunity against Listeria
Heather Knowles1, Justin W Heizer, Yuan Li
1Integrated Department of Immunology, National Jewish Health and University of Colorado, Denver, CO 80206, USA.
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.
Insights
Mice lacking the TRPM2 ion channel show severe susceptibility to Listeria monocytogenes infection due to impaired innate immunity. Restoring IFNγ levels reversed this susceptibility, highlighting TRPM2
Area of Science:
- Immunology
- Ion Channels
- Microbial Pathogenesis
Background:
- Reactive oxygen species (ROS) are vital for immune responses and host defense.
- The Transient Receptor Potential Melastatin 2 (TRPM2) channel is activated by ADP-ribose, a ROS-associated metabolite.
- TRPM2 plays a role in regulating calcium permeability and cellular signaling during immune responses.
Purpose of the Study:
- To investigate the role of the TRPM2 ion channel in innate immunity against Listeria monocytogenes (Lm) infection.
- To determine the impact of TRPM2 deficiency on immune cell function and cytokine production during Lm infection.
- To explore the therapeutic potential of targeting TRPM2 in infectious diseases.
Main Methods:
- Utilized TRPM2-deficient mice and compared their response to Lm infection with wild-type and IFNγR-deficient mice.
- Assessed bacterial replication, immune cell activation (monocytes), and levels of key cytokines (IL-12, IFNγ).
- Administered recombinant IFNγ to TRPM2-deficient mice to evaluate its therapeutic effect on Lm infection.
Main Results:
- TRPM2-deficient mice exhibited extreme susceptibility to Lm infection with inefficient innate immune responses.
- These mice showed uncontrolled bacterial growth and reduced levels of inducible nitric oxide synthase (iNOS)-expressing monocytes.
- Diminished IL-12 and IFNγ levels were observed in TRPM2(-/-) mice, correlating with reduced innate activation.
- Supplementation with recombinant IFNγ successfully reversed bacterial growth and lethality in TRPM2(-/-) mice.
Conclusions:
- TRPM2 plays a critical, previously unrecognized role in innate immunity against bacterial infections.
- ROS-mediated cation flux through TRPM2 is essential for effective host defense.
- TRPM2 represents a potential novel target for immunomodulatory interventions in infectious diseases.
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