title: Dendritic cell maturation and chemotaxis is regulated by TRPM2-mediated lysosomal Ca2+ release.
abstract: 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.
authors.affiliation: Laboratory of Cell and Molecular Signaling, Center for Biomedical Research, Queen's Medical Center, Honolulu, Hawaii, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Sumoza-Toledo
authors.forename: Ingo
authors.initials: I
authors.lastname: Lange
authors.forename: Hanna
authors.initials: H
authors.lastname: Cortado
authors.forename: Harivadan
authors.initials: H
authors.lastname: Bhagat
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Andrea
authors.initials: A
authors.lastname: Fleig
authors.forename: Reinhold
authors.initials: R
authors.lastname: Penner
authors.forename: Santiago
authors.initials: S
authors.lastname: Partida-Sánchez
mesh_terms: D000246:Adenosine Diphosphate Ribose; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D018925:Chemokines / Q000494:pharmacology; D002633:Chemotaxis / Q000502:physiology*; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D058847:Inflammasomes / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D050053:TRPM Cation Channels / Q000378:metabolism*
chemical_list: D018925:Chemokines; D058847:Inflammasomes; D053496:Inositol 1,4,5-Trisphosphate Receptors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; D000246:Adenosine Diphosphate Ribose; D002118:Calcium