TRPM2 contributes to antigen-stimulated Ca²⁺ influx in mucosal mast cells.
Food allergy (FA) is a common allergic disease without any currently available effective drug therapies. Mucosal mast cells (MMCs) play a particularly important role in FA, and the increase in their cytosolic Ca(2+) concentration ([Ca(2+)]cyt) is considered to be a principal component of the degranulation process. However, the mechanisms governing Ca(2+) influx remain poorly understood in MMCs. Recent reports have highlighted the functions of the transient receptor potential melastatin 2 (TRPM2) channel in immunocytes, including its role in monocyte chemokine production and macrophage phagocytic activity. Although TRPM2 gene expression has been demonstrated in mast cells, the significance of such expression remains virtually unknown. In this study, we found that antigen-stimulated degranulation was significantly reduced in mucosal-type bone marrow-derived mast cells (mBMMCs) prepared from TRPM2-knockout (TRPM2-KO) mice (TRPM2-KO mBMMCs) and was suppressed following the administration of three TRPM2 inhibitors with different chemical structures, including econazole, flufenamic acid (FFA), and 2-aminoethoxydiphenyl borate. Furthermore, the antigen-stimulated increase in [Ca(2+)]cyt was significantly decreased in TRPM2-KO mBMMCs and was also suppressed by the TRPM2 inhibitors econazole and FFA. In addition, thapsigargin-induced increase in [Ca(2+)]cyt was significantly decreased in TRPM2-KO mBMMCs. These results suggest that TRPM2 may participate in antigen-induced extracellular Ca(2+) influx and subsequent degranulation. In addition, TRPM2 inhibitors were shown to improve food allergic reactions in a mouse model. Together, these results suggest that TRPM2 inhibitors suppress MMC degranulation via regulation of the increase in [Ca(2+)]cyt. Thus, TRPM2 may play a key role in degranulation by modulating intracellular Ca(2+) in MMCs.
Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Satoshi
S
Oda
Kunitoshi
K
Uchida
Xiaoyu
X
Wang
Jaemin
J
Lee
Yutaka
Y
Shimada
Makoto
M
Tominaga
Makoto
M
Kadowaki
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000941:Antigens / Q000276:immunology*; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D015550:Cell Degranulation; D004464:Econazole / Q000494:pharmacology / Q000627:therapeutic use; D005439:Flufenamic Acid / Q000494:pharmacology / Q000627:therapeutic use; D005512:Food Hypersensitivity / Q000188:drug therapy / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000166:cytology; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D000941:Antigens; D001896:Boron Compounds; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; D005439:Flufenamic Acid; D004464:Econazole; C109986:2-aminoethoxydiphenyl borate; D002118:Calcium