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TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration

Abstract

Reactive oxygen species (ROS) induce chemokines responsible for the recruitment of inflammatory cells to sites of injury or infection. Here we show that the plasma membrane Ca2+-permeable channel TRPM2 controls ROS-induced chemokine production in monocytes. In human U937 monocytes, hydrogen peroxide (H2O2) evokes Ca2+ influx through TRPM2 to activate Ca2+-dependent tyrosine kinase Pyk2 and amplify Erk signaling via Ras GTPase. This elicits nuclear translocation of nuclear factor-κB essential for the production of the chemokine interleukin-8 (CXCL8). In monocytes from Trpm2-deficient mice, H2O2-induced Ca2+ influx and production of the macrophage inflammatory protein-2 (CXCL2), the mouse CXCL8 functional homolog, were impaired. In the dextran sulfate sodium-induced colitis inflammation model, CXCL2 expression, neutrophil infiltration and ulceration were attenuated by Trpm2 disruption. Thus, TRPM2 Ca2+ influx controls the ROS-induced signaling cascade responsible for chemokine production, which aggravates inflammation. We propose functional inhibition of TRPM2 channels as a new therapeutic strategy for treating inflammatory diseases.

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Figure 1: Erk-, NF-κB– and TRPM2-mediated Ca2+ entry control H2O2-induced CXCL8 expression in U937 cells.
Figure 2: TRPM2-mediated Ca2+ influx controls H2O2-induced nuclear translocation of NF-κB via Erk in U937 cells.
Figure 3: TRPM2-mediated Ca2+ influx activates Pyk2 and Ras to amplify Erk signal in U937 cells.
Figure 4: TRPM2 currents activated by ADPR and H2O2 are disrupted in Trpm2-knockout monocytes.
Figure 5: H2O2-induced CXCL2 production and the underlying signal transduction are impaired in Trpm2 KO monocytes.
Figure 6: Trpm2 deficiency suppresses exacerbation of inflammation in colitis mouse model.

References

  1. 1

    Luster, A.D. Chemokines—chemotactic cytokines that mediate inflammation. N. Engl. J. Med. 338, 436–445 (1998).

    CAS  Article  Google Scholar 

  2. 2

    Sonoda, Y. et al. Physiologic regulation of postovulatory neutrophil migration into vagina in mice by a C-X-C chemokine(s). J. Immunol. 6159–6165 (1998).

  3. 3

    Fialkow, L., Wang, Y. & Downey, G.P. Reactive oxygen and nitrogen species as signaling molecules regulating neutrophil function. Free Radic. Biol. Med. 42, 153–164 (2007).

    CAS  Article  Google Scholar 

  4. 4

    Henricks, P.A.J. & Nijkamp, F.P. Reactive oxygen species as mediators in asthma. Pulm. Pharmacol. Ther. 14, 409–421 (2001).

    CAS  Article  Google Scholar 

  5. 5

    Dröge, W. Free radicals in the physiological control of cell function. Physiol. Rev. 82, 47–95 (2002).

    Article  Google Scholar 

  6. 6

    Cavaillon, J.M. & Adib-Conquy, M. Monocytes/macrophages and sepsis. Crit. Care Med. 33, S506–S509 (2005).

    Article  Google Scholar 

  7. 7

    Josse, C., Boelaert, J.R., Best-Belpomme, M. & Piette, J. Importance of post-transcriptional regulation of chemokine genes by oxidative stress. Biochem. J. 360, 321–333 (2001).

    CAS  Article  Google Scholar 

  8. 8

    Zeng, X., Dai, J., Remick, D.G. & Wang, X. Homocysteine mediated expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human monocytes. Circ. Res. 93, 311–320 (2003).

    CAS  Article  Google Scholar 

  9. 9

    Feske, S., Giltnane, J., Dolmetsch, R., Staudt, L.M. & Rao, A. Gene regulation mediated by calcium signals in T lymphocytes. Nat. Immunol. 2, 316–324 (2001).

    CAS  Article  Google Scholar 

  10. 10

    Wilson, L., Butcher, C.J. & Kellie, S. Calcium ionophore A23187 induces interleukin-8 gene expression and protein secretion in human monocytic cells. FEBS Lett. 325, 295–298 (1993).

    CAS  Article  Google Scholar 

  11. 11

    Méndez-Samperio, P., Palma-Barrios, J., Vázquez-Hernández, A. & García-Martinez, E. Secretion of interleukin-8 by human-derived cell lines infected with Mycobacterium bovis. Mediators Inflamm. 13, 45–49 (2004).

    Article  Google Scholar 

  12. 12

    Clapham, D.E. TRP channels as cellular sensors. Nature 426, 517–524 (2003).

    CAS  Article  Google Scholar 

  13. 13

    Perraud, A.L. et al. ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature 411, 595–599 (2001).

    CAS  Article  Google Scholar 

  14. 14

    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).

    CAS  Article  Google Scholar 

  15. 15

    Massullo, P., Sumoza-Toledo, A., Bhagat, H. & Partida-Sánchez, S. TRPM channels, calcium and redox sensors during innate immune responses. Semin. Cell Dev. Biol. 17, 654–666 (2006).

    CAS  Article  Google Scholar 

  16. 16

    Perraud, A.L. et al. Accumulation of free ADP-ribose from mitochondria mediates oxidative stress–induced gating of TRPM2 cation channels. J. Biol. Chem. 280, 6138–6148 (2005).

    CAS  Article  Google Scholar 

  17. 17

    Kaneko, S. et al. A critical role of TRPM2 in neuronal cell death by hydrogen peroxide. J. Pharmacol. Sci. 101, 66–76 (2006).

    CAS  Article  Google Scholar 

  18. 18

    Korenaga, D. et al. Impaired antioxidant defense system of colonic tissue and cancer development in dextran sulfate sodium–induced colitis in mice. J. Surg. Res. 102, 144–149 (2002).

    CAS  Article  Google Scholar 

  19. 19

    Blackburn, A.C., Doe, W.F. & Buffinton, G.D. Salicylate hydroxylation as an indicator of hydroxyl radical generation in dextran sulfate–induced colitis. Free Radic. Biol. Med. 25, 305–313 (1998).

    CAS  Article  Google Scholar 

  20. 20

    Araki, Y., Sugihara, H. & Hattori, T. The free radical scavengers edaravone and tempol suppress experimental dextran sulfate sodium–induced colitis in mice. Int. J. Mol. Med. 17, 331–334 (2006).

    CAS  PubMed  Google Scholar 

  21. 21

    Chiu, L.L., Perng, D.W., Yu, C.H., Su, S.N. & Chow, L.P. Mold allergen, pen C 13, induces IL-8 expression in human airway epithelial cells by activating protease-activated receptor 1 and 2. J. Immunol. 178, 5237–5244 (2007).

    CAS  Article  Google Scholar 

  22. 22

    Mizukami, Y. et al. Induction of interleukin-8 preserves the angiogenic response in HIF-1α–deficient colon cancer cells. Nat. Med. 11, 992–997 (2005).

    CAS  Article  Google Scholar 

  23. 23

    Yoshida, T. et al. Nitric oxide activates TRP channels by cysteine S-nitrosylation. Nat. Chem. Biol. 2, 596–607 (2006).

    CAS  Article  Google Scholar 

  24. 24

    Dejardin, E. et al. The lymphotoxin-β receptor induces different patterns of gene expression via two NF-κB pathways. Immunity 17, 525–535 (2002).

    CAS  Article  Google Scholar 

  25. 25

    Lev, S. et al. Protein tyrosine kinase PYK2 involved in Ca2+-induced regulation of ion channel and MAP kinase functions. Nature 376, 737–745 (1995).

    CAS  Article  Google Scholar 

  26. 26

    Roose, J.P., Mollenauer, M., Gupta, V.A., Stone, J. & Weiss, A. A diacylglycerol-protein kinase C-RasGRP1 pathway directs Ras activation upon antigen receptor stimulation of T cells. Mol. Cell. Biol. 25, 4426–4441 (2005).

    CAS  Article  Google Scholar 

  27. 27

    Jaramillo, M. & Olivier, M. Hydrogen peroxide induces murine macrophage chemokine gene transcription via extracellular signal-regulated kinase– and cyclic adenosine 5′-monophosphate (cAMP)–dependent pathways: involvement of NF-κB, activator protein 1, and cAMP response element binding protein. J. Immunol. 169, 7026–7038 (2002).

    CAS  Article  Google Scholar 

  28. 28

    Gloire, G., Legrand-Poels, S. & Piette, J. NF-κB activation by reactive oxygen species: fifteen years later. Biochem. Pharmacol. 72, 1493–1505 (2006).

    CAS  Article  Google Scholar 

  29. 29

    Kim, D.-S., Han, J.H. & Kwon, H.J. NF-κB and c-Jun–dependent regulation of macrophage inflammatory protein-2 gene expression in response to lipopolysaccharide in RAW 264.7 cells. Mol. Immunol. 40, 633–643 (2003).

    CAS  Article  Google Scholar 

  30. 30

    Ohtsuka, Y. & Sanderson, I.R. Dextran sulfate sodium–induced inflammation is enhanced by intestinal epithelial cell chemokine expression in mice. Pediatr. Res. 53, 143–147 (2003).

    CAS  PubMed  Google Scholar 

  31. 31

    Saklatvala, J. The p38 MAP kinase pathway as a therapeutic target in inflammatory disease. Curr. Opin. Pharmacol. 4, 372–377 (2004).

    CAS  Article  Google Scholar 

  32. 32

    Lee, K. & Esselman, W.J. cAMP potentiates H2O2-induced ERK1/2 phosphorylation without the requirement for MEK1/2 phosphorylation. Cell. Signal. 13, 645–652 (2001).

    CAS  Article  Google Scholar 

  33. 33

    Seimiya, H. & Tsuruo, T. Differential expression of protein tyrosine phosphatase genes during phorbol ester–induced differentiation of human leukemia U937 cells. Cell Growth Differ. 4, 1033–1039 (1993).

    CAS  PubMed  Google Scholar 

  34. 34

    Zhang, W. et al. Regulation of TRP channel TRPM2 by the tyrosine phosphatase PTPL1. Am. J. Physiol. Cell Physiol. 292, C1746–C1758 (2007).

    CAS  Article  Google Scholar 

  35. 35

    Lambeth, J.D. NOX enzymes and the biology of reactive oxygen. Nat. Rev. Immunol. 4, 181–189 (2004).

    CAS  Article  Google Scholar 

  36. 36

    Khor, T.O. et al. Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium–induced colitis. Cancer Res. 66, 11580–11584 (2006).

    CAS  Article  Google Scholar 

  37. 37

    Han, X.B., Liu, X., Hsueh, W. & De Plaen, I.G. Macrophage inflammatory protein-2 mediates the bowel injury induced by platelet-activating factor. Am. J. Physiol. Gastrointest. Liver Physiol. 287, G1220–G1226 (2004).

    CAS  Article  Google Scholar 

  38. 38

    Buanne, P. et al. Crucial pathophysiological role of CXCR2 in experimental ulcerative colitis in mice. J. Leukoc. Biol. 82, 1239–1246 (2007).

    CAS  Article  Google Scholar 

  39. 39

    Keshavarzian, A. et al. Increased interleukin-8 (IL-8) in rectal dialysate from patients with ulcerative colitis: evidence for a biological role for IL-8 in inflammation of the colon. Am. J. Gastroenterol. 94, 704–712 (1999).

    CAS  Article  Google Scholar 

  40. 40

    Anezaki, K. et al. Correlations between interleukin-8, and myeloperoxidase or luminol-dependent chemiluminescence in inflamed mucosa of ulcerative colitis. Intern. Med. 37, 253–258 (1998).

    CAS  Article  Google Scholar 

  41. 41

    Grip, O., Janciauskiene, S. & Lindgren, S. Macrophages in inflammatory bowel disease. Curr. Drug Targets Inflamm. Allergy 2, 155–160 (2003).

    CAS  Article  Google Scholar 

  42. 42

    Smith, P.D., Ochsenbauer-Jambor, C. & Smythies, L.E. Intestinal macrophages: unique effector cells of the innate immune system. Immunol. Rev. 206, 149–159 (2005).

    CAS  Article  Google Scholar 

  43. 43

    Mahida, Y.R. The key role of macrophages in the immunopathogenesis of inflammatory bowel disease. Inflamm. Bowel Dis. 6, 21–33 (2000).

    CAS  Article  Google Scholar 

  44. 44

    Videla, L.A., Fernández, V., Tapia, G. & Varela, P. Oxidative stress–mediated hepatotoxicity of iron and copper: role of Kupffer cells. Biometals 16, 103–111 (2003).

    CAS  Article  Google Scholar 

  45. 45

    Barnes, P.J. COPD: is there light at the end of the tunnel? Curr. Opin. Pharmacol. 4, 263–272 (2004).

    CAS  Article  Google Scholar 

  46. 46

    Hermosura, M.C. & Garruto, R.M. TRPM7 and TRPM2—candidate susceptibility genes for Western Pacific ALS and PD? Biochim. Biophys. Acta 1772, 822–835 (2007).

    CAS  Article  Google Scholar 

  47. 47

    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).

    CAS  Article  Google Scholar 

  48. 48

    Cuzzocrea, S. et al. Role of poly(ADP-ribose) glycohydrolase in the development of inflammatory bowel disease in mice. Free Radic. Biol. Med. 42, 90–105 (2007).

    CAS  Article  Google Scholar 

  49. 49

    Haskó, G. et al. Poly(ADP-ribose) polymerase is a regulator of chemokine production: relevance for the pathogenesis of shock and inflammation. Mol. Med. 8, 283–289 (2002).

    Article  Google Scholar 

  50. 50

    Partida-Sánchez, S. et al. Cyclic ADP-ribose production by CD38 regulates intracellular calcium release, extracellular calcium influx and chemotaxis in neutrophils and is required for bacterial clearance in vivo. Nat. Med. 7, 1209–1216 (2001).

    Article  Google Scholar 

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Acknowledgements

We thank T. Niidome, T. Nakagawa and H. Shirakawa for their support in mouse experiments and M. Hikida, T. Yamazaki and K. Takahara for helpful advice. This study was supported by research grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, the Japan Society for the Promotion of Science, Japan Science and Technology Agency, and the US National Institutes of Health.

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S.Y., acquisition, analysis and interpretation of data and drafting of the manuscript; S.S., S. Kiyonaka, N.T., T.W., Y.H., T.N., T.H., T.O., I.L., A.F. and M.N., acquisition, analysis and interpretation of data; Y.K., S. Kaneko, R.P. and H.T., analysis and interpretation of data; Y.M., analysis and interpretation of data and drafting and critical review of the manuscript.

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Correspondence to Yasuo Mori.

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Yamamoto, S., Shimizu, S., Kiyonaka, S. et al. TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nat Med 14, 738–747 (2008). https://doi.org/10.1038/nm1758

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