Access

Nature Medicine 14, 738-747 (1 July 2008) | doi:10.1038/nm1758;

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

Shinichiro Yamamoto , Shunichi Shimizu , Shigeki Kiyonaka , Nobuaki Takahashi , Teruaki Wajima , Yuji Hara , Takaharu Negoro , Toshihito Hiroi , Yuji Kiuchi , Takaharu Okada , Shuji Kaneko , Ingo Lange , Andrea Fleig , Reinhold Penner , Miyuki Nishi , Hiroshi Takeshima & Yasuo Mori

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.

$rb.Type.Code