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Dendritic cell maturation and chemotaxis is regulated by TRPM2‐mediated lysosomal Ca 2+ release
Author(s) -
SumozaToledo Adriana,
Lange Ingo,
Cortado Hanna,
Bhagat Harivadan,
Mori Yasuo,
Fleig Andrea,
Penner Reinhold,
PartidaSánchez Santiago
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-178483
Subject(s) - trpm2 , chemotaxis , microbiology and biotechnology , transient receptor potential channel , chemokine , calcium signaling , intracellular , receptor , chemistry , biology , biochemistry
Chemokines induce calcium (Ca 2+ ) signaling and chemotaxis in dendritic cells (DCs), but the molecular players involved in shaping intracellular Ca 2+ changes remain to be characterized. Using siRNA and knockout mice, we show that in addition to inositol 1,4,5‐trisphosphate (IP 3 )‐mediated Ca 2+ release and store‐operated Ca 2+ entry (SOCE), the transient receptor potential melastatin 2 (TRPM2) channel contributes to Ca 2+ release but not Ca 2+ influx in mouse DCs. Consistent with these findings, TRPM2 expression in DCs is restricted to endolysosomal vesicles, whereas in neutrophils, the channel localizes to the plasma membrane. TRPM2‐deficient DCs show impaired maturation and severely compromised chemokine‐activated directional migration as well as bacterial‐induced DC trafficking to the draining lymph nodes. Defective DC chemotaxis is due to perturbed chemokine‐receptor‐initiated Ca 2+ signaling mechanisms, which include suppression of TRPM2‐mediated Ca 2+ release and secondary modification of SOCE. DCs deficient in both TRPM2 and IP 3 receptor signaling lose their ability to perform chemotaxis entirely. These results highlight TRPM2 as a key player regulating DC chemotaxis through its function as Ca 2+ release channel and confirm ADP‐ribose as a novel second messenger for intracellular Ca 2+ mobilization.—Sumoza‐Toledo, A., Lange, I., Cortado, H., Bhagat, H., Mori, Y., Fleig, A., Penner, R., Partida‐Sánchez, S. Dendritic cell maturation and chemotaxis is regulated by TRPM2‐mediated lysosomal Ca 2+ release. FASEB J. 25, 3529–3542 (2011). www.fasebj.org