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TRPV2 has a pivotal role in macrophage particle binding and phagocytosis

Nature Immunology volume 11, pages 232–239 (2010)Cite this article

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Abstract

Macrophage phagocytosis is critical for defense against pathogens. Whereas many steps of phagocytosis involve ionic flux, the underlying ion channels remain ill defined. Here we show that zymosan-, immunoglobulin G (IgG)- and complement-mediated particle binding and phagocytosis were impaired in macrophages lacking the cation channel TRPV2. TRPV2 was recruited to the nascent phagosome and depolarized the plasma membrane. Depolarization increased the synthesis of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), which triggered the partial actin depolymerization necessary for occupancy-elicited phagocytic receptor clustering. TRPV2-deficient macrophages were also defective in chemoattractant-elicited motility. Consequently, TRPV2-deficient mice showed accelerated mortality and greater organ bacterial load when challenged with Listeria monocytogenes. Our data demonstrate the participation of TRPV2 in early phagocytosis and its fundamental importance in innate immunity.

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Figure 1: TRPV2 expression in phagocyte populations.
Figure 2: TRPV2 Ca2+ influx responses and function in macrophage chemotaxis and cytokine release.
Figure 3: Defective phagocytosis and particle binding across diverse substrates in TRPV2-deficient macrophages.
Figure 4: Translocation of TRPV2 to developing phagosomes and FcγR clustering.
Figure 5: TRPV2-dependent depolarization regulates particle binding and FcγR clustering.
Figure 6: Depolarization and actin depolymerization regulate FcγR clustering.
Figure 7: Impaired bacterial phagocytosis by TRPV2 deficient macrophages in vitro and enhanced in vivo susceptibility of TRPV2-deficient mice to bacterial infection.

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Acknowledgements

We thank J. Brederson, M.-K. Chung, S. Huang, M. Meffert, C. Munns and V. Vega for suggestions; J. Wang and S. Li for technical assistance; S. Hudson for help with flow cytometry; P. Devreotes (Johns Hopkins School of Medicine) for suggestions and latrunculin A; and W. Bishai and S. Huang for critically reading the manuscript. Supported by the National Institutes of Health (R01NS051551 to MJC, RO1AI42287-05 to M.J.S.; AI059298 and AI071117 to B.M.V.; GM059251 to D.M.R.; and a Medical Scientist Training Program Award to T.M.L.).

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Authors and Affiliations

  1. Department of Biological Chemistry, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

    Tiffany M Link, Una Park, Daniel M Raben & Michael J Caterina

  2. Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

    Tiffany M Link, Una Park & Michael J Caterina

  3. Center for Sensory Biology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

    Tiffany M Link, Una Park & Michael J Caterina

  4. Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

    Becky M Vonakis

  5. Department of Medicine, Division of Rheumatology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

    Mark J Soloski

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Contributions

T.M.L. did most of the experiments; U.P. generated TRPV2-deficient mice, did some immunolocalization experiments and contributed to study design; B.M.V. contributed to study design for in vitro macrophage characterization and pathway delineation; M.J.S. contributed to study design for L. monocytogenes experiments and interpretation of flow cytometry data; D.M.R. contributed to study design for phospholipid metabolism; M.J.C. did some immunolocalization; T.M.L. and M.J.C. designed the study, analyzed data and wrote the manuscript; and all authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Michael J Caterina.

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Competing interests

Under a licensing agreement between Merck and University of California at San Francisco, M.J.C. is entitled to a share of royalties received for sales of products used in the study described in this article. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

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Link, T., Park, U., Vonakis, B. et al. TRPV2 has a pivotal role in macrophage particle binding and phagocytosis. Nat Immunol 11, 232–239 (2010). https://doi.org/10.1038/ni.1842

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