Abstract
The NADPH oxidase activity of phagocytes and its generation of reactive oxygen species (ROS) is critical for host defense, but ROS overproduction can also lead to inflammation and tissue injury. Here we report that TRPM2, a nonselective and redox-sensitive cation channel, inhibited ROS production in phagocytic cells and prevented endotoxin-induced lung inflammation in mice. TRPM2-deficient mice challenged with endotoxin (lipopolysaccharide) had an enhanced inflammatory response and diminished survival relative to that of wild-type mice challenged with endotoxin. TRPM2 functioned by dampening NADPH oxidase–mediated ROS production through depolarization of the plasma membrane in phagocytes. As ROS also activate TRPM2, our findings establish a negative feedback mechanism for the inactivation of ROS production through inhibition of the membrane potential–sensitive NADPH oxidase.
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Change history
03 February 2012
In the version of this article initially published, the description of the Trpm2−/− mice in the first paragraph of the Online Methods was incomplete. That section should read as follows: "Trpm2−/− mice (obtained from B.A. Miller) were generated and originally provided by GlaxoSmithKline46. Another group has independently generated Trpm2−/− mice12; those were not used here." The new reference (46) is as follows: Knowles, H. et al. Transient receptor potential melastatin 2 (TRPM2) ion channel is required for innate immunity against Listeria monocytogenes. Proc. Natl. Acad. Sci. USA 108, 11578–11583 (2011). The error has been corrected in the HTML and PDF versions of the article.
References
Iles, K.E. & Forman, H.J. Macrophage signaling and respiratory burst. Immunol. Res. 26, 95–105 (2002).
Gwinn, M.R. & Vallyathan, V. Respiratory burst: role in signal transduction in alveolar macrophages. J. Toxicol. Environ. Health B Crit. Rev. 9, 27–39 (2006).
DeCoursey, T.E. Voltage-gated proton channels find their dream job managing the respiratory burst in phagocytes. Physiology (Bethesda) 25, 27–40 (2010).
DeCoursey, T.E., Morgan, D. & Cherny, V.V. The voltage dependence of NADPH oxidase revealss why phagocytes need proton channels. Nature 422, 531–534 (2003).
Fontayne, A., Dang, P.M., Gougerot-Pocidalo, M.A. & El-Benna, J. Phosphorylation of p47phox sites by PKC alpha, beta II, delta, and zeta: effect on binding to p22phox and on NADPH oxidase activation. Biochemistry 41, 7743–7750 (2002).
Cathcart, M.K. Regulation of superoxide anion production by NADPH oxidase in monocytes/macrophages: contributions to atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 24, 23–28 (2004).
Nagamine, K. et al. Molecular cloning of a novel putative Ca2+ channel protein (TRPC7) highly expressed in brain. Genomics 54, 124–131 (1998).
Sano, Y. et al. Immunocyte Ca2+ influx system mediated by LTRPC2. Science 293, 1327–1330 (2001).
Owsianik, G., Talavera, K., Voets, T. & Nilius, B. Permeation and selectivity of TRP channels. Annu. Rev. Physiol. 68, 685–717 (2006).
Hecquet, C.M., Ahmmed, G.U., Vogel, S.M. & Malik, A.B. Role of TRPM2 channel in mediating H2O2-induced Ca2+ entry and endothelial hyperpermeability. Circ. Res. 102, 347–355 (2008).
Lange, I. et al. TRPM2 functions as a lysosomal Ca2+-release channel in beta cells. Sci. Signal. 2, ra23 (2009).
Yamamoto, S. et al. TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nat. Med. 14, 738–747 (2008).
Guo, R.F. & Ward, P.A. Role of oxidants in lung injury during sepsis. Antioxid. Redox Signal. 9, 1991–2002 (2007).
Chow, C.W., Herrera Abreu, M.T., Suzuki, T. & Downey, G.P. Oxidative stress and acute lung injury. Am. J. Respir. Cell Mol. Biol. 29, 427–431 (2003).
Cross, A.R. & Jones, O.T. The effect of the inhibitor diphenylene iodonium on the superoxide-generating system of neutrophils. Specific labelling of a component polypeptide of the oxidase. Biochem. J. 237, 111–116 (1986).
Fonfria, E. et al. TRPM2 channel opening in response to oxidative stress is dependent on activation of poly(ADP-ribose) polymerase. Br. J. Pharmacol. 143, 186–192 (2004).
Suto, M.J., Turner, W.R., Arundel-Suto, C.M., Werbel, L.M. & Sebolt-Leopold, J.S. Dihydroisoquinolinones: the design and synthesis of a new series of potent inhibitors of poly(ADP-ribose) polymerase. Anticancer Drug Des. 6, 107–117 (1991).
Ding, Y. et al. Overexpression of peroxiredoxin 4 protects against high-dose streptozotocin-induced diabetes by suppressing oxidative stress and cytokines in transgenic mice. Antioxid. Redox Signal. 13, 1477–1490 (2010).
Khan, S.J. et al. Stress-induced senescence exaggerates postinjury neointimal formation in the old vasculature. Am. J. Physiol. Heart Circ. Physiol. 298, H66–H74 (2010).
Murphy, R. & DeCoursey, T.E. Charge compensation during the phagocyte respiratory burst. Biochim. Biophys. Acta 1757, 996–1011 (2006).
Kelkar, D.A. & Chattopadhyay, A. The gramicidin ion channel: a model membrane protein. Biochim. Biophys. Acta 1768, 2011–2025 (2007).
El Chemaly, A. et al. VSOP/Hv1 proton channels sustain calcium entry, neutrophil migration, and superoxide production by limiting cell depolarization and acidification. J. Exp. Med. 207, 129–139 (2010).
Minke, B. & Cook, B. TRP channel proteins and signal transduction. Physiol. Rev. 82, 429–472 (2002).
Venkatachalam, K. & Montell, C. TRP channels. Annu. Rev. Biochem. 76, 387–417 (2007).
Pedersen, S.F., Owsianik, G. & Nilius, B. TRP channels: an overview. Cell Calcium 38, 233–252 (2005).
Miller, B.A. The role of TRP channels in oxidative stress-induced cell death. J. Membr. Biol. 209, 31–41 (2006).
Hara, Y. et al. LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. Mol. Cell 9, 163–173 (2002).
Wehage, E. et al. Activation of the cation channel long transient receptor potential channel 2 (LTRPC2) by hydrogen peroxide. A splice variant reveals a mode of activation independent of ADP-ribose. J. Biol. Chem. 277, 23150–23156 (2002).
Randriamampita, C. & Trautmann, A. Biphasic increase in intracellular calcium induced by platelet-activating factor in macrophages. FEBS Lett. 249, 199–206 (1989).
Swain, S.D. et al. Platelet-activating factor induces a concentration-dependent spectrum of functional responses in bovine neutrophils. J. Leukoc. Biol. 64, 817–827 (1998).
Vennekens, R. et al. Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4. Nat. Immunol. 8, 312–320 (2007).
Nilius, B. et al. Voltage dependence of the Ca2+-activated cation channel TRPM4. J. Biol. Chem. 278, 30813–30820 (2003).
Colquhoun, D., Neher, E., Reuter, H. & Stevens, C.F. Inward current channels activated by intracellular Ca in cultured cardiac cells. Nature 294, 752–754 (1981).
Prawitt, D. et al. TRPM5 is a transient Ca2+-activated cation channel responding to rapid changes in [Ca2+]i . Proc. Natl. Acad. Sci. USA 100, 15166–15171 (2003).
Launay, P. et al. TRPM4 is a Ca2+-activated nonselective cation channel mediating cell membrane depolarization. Cell 109, 397–407 (2002).
Sumoza-Toledo, A. et al. Dendritic cell maturation and chemotaxis is regulated by TRPM2-mediated lysosomal Ca2+ release. FASEB J. 25, 3529–3542 (2011).
Sumoza-Toledo, A. & Penner, R. TRPM2: a multifunctional ion channel for calcium signaling. J. Physiol. (Lond.) 589, 1515–1525 (2011).
Schrenzel, J. et al. Electron currents generated by the human phagocyte NADPH oxidase. Nature 392, 734–737 (1998).
Klebanoff, S.J. Oxygen metabolism and the toxic properties of phagocytes. Ann. Intern. Med. 93, 480–489 (1980).
Bankers-Fulbright, J.L., Gleich, G.J., Kephart, G.M., Kita, H. & O'Grady, S.M. Regulation of eosinophil membrane depolarization during NADPH oxidase activation. J. Cell Sci. 116, 3221–3226 (2003).
Petheo, G.L. & Demaurex, N. Voltage- and NADPH-dependence of electron currents generated by the phagocytic NADPH oxidase. Biochem. J. 388, 485–491 (2005).
Demaurex, N. & Elchemaly, A. Physiological roles of voltage-gated proton channels in leukocytes. J. Physiol. 588, 4659–4665 (2010).
Buckley, J.F., Singer, M. & Clapp, L.H. Role of KATP channels in sepsis. Cardiovasc. Res. 72, 220–230 (2006).
Zorn-Pauly, K. et al. Endotoxin impairs the human pacemaker current If. Shock 28, 655–661 (2007).
Umans, J.G., Salvi, D., Murray, P.T. & Wylam, M.E. Selectivity of endotoxin-induced defect in endothelial calcium mobilization. Kidney Int. 54, 1063–1069 (1998).
Knowles, K. Transient receptor potential melastatin 2 (TRPM2) ion channel is required for innate immunity against Listeria monocytogenes. Proc. Natl. Acad. Sci. USA 108, 11578–11583 (2011).
Zhang, X., Goncalves, R. & Mosser, D.M. in Current Protocols in Immunology (eds. Coligan, J.E., Bierer, B.E., Margulies, D.H., Shevach, E.M. & Strober, W.) Ch 14, Unit 14 1 (John Wiley & Sons, Chichester, UK, 2008).
Xu, J. et al. Nonmuscle myosin light-chain kinase mediates neutrophil transmigration in sepsis-induced lung inflammation by activating β2 integrins. Nat. Immunol. 9, 880–886 (2008).
Garrean, S. et al. Caveolin-1 regulates NF-κB activation and lung inflammatory response to sepsis induced by lipopolysaccharide. J. Immunol. 177, 4853–4860 (2006).
Gao, X.P. et al. Blockade of class IA phosphoinositide 3-kinase in neutrophils prevents NADPH oxidase activation- and adhesion-dependent inflammation. J. Biol. Chem. 282, 6116–6125 (2007).
Di, A., Krupa, B. & Nelson, D.J. Calcium-G protein interactions in the regulation of macrophage secretion. J. Biol. Chem. 276, 37124–37132 (2001).
Acknowledgements
We thank T.E. DeCoursey, N. Demaurex, J.D. Lambeth and M.C. Dinauer for insights; B.A. Miller (Pennsylvania State University School of Medicine) for Trpm2−/− C57BL/6 mice; and G. Liu and G. Wang for technical assistance. Supported by the Francis Families Foundation (Parker B. Francis Fellowship Program, 2007−2010) and the US National Institutes of Health (P01 HL77806).
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A.D. and A.B.M. designed the study; A.D., X.-P.G., F.Q., T.K., J.H., C.H. and S.M.V. did experiments and data analysis; and A.D., R.D.Y. and A.B.M. wrote the paper.
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Di, A., Gao, XP., Qian, F. et al. The redox-sensitive cation channel TRPM2 modulates phagocyte ROS production and inflammation. Nat Immunol 13, 29–34 (2012). https://doi.org/10.1038/ni.2171
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DOI: https://doi.org/10.1038/ni.2171
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