TRPM2-mediated [Ca.sup.2+] 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 [Ca.sup.2+]-permeable channel TRPM2 controls ROS-induced chemokine production in monocytes. In human U937 monocytes, hydrogen peroxide ([H.sub.2][O.sub.2]) evokes [Ca.sup.2+] influx through TRPM2 to activate [Ca.sup.2+]-dependent tyrosine kinase Pyk2 and amplify Erk signaling via Ras GTPase. This elicits nuclear translocation of nuclear factor-[kappa]B essential for the production of the chemokine interleukin-8 (CXCL8). In monocytes from Trpm2-deficient mice, [H.sub.2][O.sub.2]-induced [Ca.sup.2+] 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 [Ca.sup.2+] 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.
The biological purpose of inflammation is to bring fluids, proteins and inflammatory cells such as neutrophils and monocytes from the blood into the damaged tissues to eliminate the injuring agents [...]