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 Ca(2+)-permeable channel TRPM2 controls ROS-induced chemokine production in monocytes. In human U937 monocytes, hydrogen peroxide (H(2)O(2)) evokes Ca(2+) influx through TRPM2 to activate Ca(2+)-dependent tyrosine kinase Pyk2 and amplify Erk signaling via Ras GTPase. This elicits nuclear translocation of nuclear factor-kappaB essential for the production of the chemokine interleukin-8 (CXCL8). In monocytes from Trpm2-deficient mice, H(2)O(2)-induced Ca(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(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.
Yamamoto
Shinichiro
S
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura Campus, Nishikyo-ku, Kyoto 615-8510, Japan.
Shimizu
Shunichi
S
Kiyonaka
Shigeki
S
Takahashi
Nobuaki
N
Wajima
Teruaki
T
Hara
Yuji
Y
Negoro
Takaharu
T
Hiroi
Toshihito
T
Kiuchi
Yuji
Y
Okada
Takaharu
T
Kaneko
Shuji
S
Lange
Ingo
I
Fleig
Andrea
A
Penner
Reinhold
R
Nishi
Miyuki
M
Takeshima
Hiroshi
H
Mori
Yasuo
Y
D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D016209:Interleukin-8 / Q000096:biosynthesis*; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism*; D020556:Neutrophil Infiltration; D016877:Oxidants / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D020298:U937 Cells
D016209:Interleukin-8; D016877:Oxidants; D012333:RNA, Messenger; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D006861:Hydrogen Peroxide; D002118:Calcium