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


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.


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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).

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