Article abstract
Nature Medicine 14, 738 - 747 (2008)
Published online: 8 June 2008 | doi:10.1038/nm1758
TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration
Shinichiro Yamamoto1, Shunichi Shimizu2, Shigeki Kiyonaka1, Nobuaki Takahashi1, Teruaki Wajima1, Yuji Hara1, Takaharu Negoro3, Toshihito Hiroi2, Yuji Kiuchi2, Takaharu Okada1, Shuji Kaneko4, Ingo Lange5, Andrea Fleig5, Reinhold Penner5, Miyuki Nishi6, Hiroshi Takeshima6 & Yasuo Mori1
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-
B 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.
- Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura Campus, Nishikyo-ku, Kyoto 615-8510, Japan.
- Department of Pathophysiology, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
- Department of Medicinal Information, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimo-Adachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
- Laboratory of Cell and Molecular Signaling, Center for Biomedical Research at The Queen's Medical Center and John A. Burns School of Medicine at University of Hawaii, 1301 Punchbowl Street, Honolulu, Hawaii 96813, USA.
- Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimo-Adachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Correspondence to: Yasuo Mori1 e-mail: mori@sbchem.kyoto-u.ac.jp
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