title: Impact of engagement of FcepsilonRI and CC chemokine receptor 1 on mast cell activation and motility.
abstract: CC chemokines participate in the recruitment and activation of immune cells through CC chemokine receptors (CCRs). Here, we report that cross-talk between CCR1-mediated signaling pathway and FcepsilonRI-mediated signaling pathway affects degranulation positively but affects chemotaxis of mast cells adversely. Costimulation via FcepsilonRI engagement with IgE/antigen and CCR1 engagement with recombinant human CCL3 synergistically enhanced degranulation in rat basophilic leukemia-2H3 cells expressing human CCR1 (RBL-CCR1). Interestingly, FcepsilonRI engagement inhibited CCL3-mediated chemotaxis and membrane ruffling of RBL-CCR1 cells. Small GTP-binding proteins of the Rho family, Rac, Cdc42, and Rho control chemotaxis by mediating the reorganization of the actin cytoskeleton. Both a Rho inhibitor C3 exoenzyme and a Rho kinase (ROCK) inhibitor Y-27632 inhibited chemotaxis of RBL-CCR1 cells toward CCL3, indicating that activation of the Rho/ROCK signaling pathway is required for the CCL3-mediated chemotaxis of the cells. Costimulation with IgE/antigen and CCL3 enhanced Rac and Cdc42 activation but decreased ROCK activation in RBL-CCR1 cells compared with that in the cells stimulated with CCL3 alone. These results suggest that costimulation via FcepsilonRI and CCR1 engagements induced 1) inhibition of membrane ruffling, 2) decreased ROCK activation, and 3) reciprocal imbalance between Small GTP-binding proteins of the Rho family, which result in the inhibition of chemotaxis of RBL-CCR1 cells. The cross-talk between FcepsilonRI-mediated signaling pathway and CCR-mediated signaling pathway would induce optimal activation and arrested chemotaxis of mast cells, thus contributing to allergic inflammation.
authors.affiliation: Division of Ocular Immunology, Institutes of Ophthalmology, University College London, London EC1V 9EL, United Kingdom.
authors.forename: Masako
authors.initials: M
authors.lastname: Toda
authors.forename: Maria
authors.initials: M
authors.lastname: Dawson
authors.forename: Takao
authors.initials: T
authors.lastname: Nakamura
authors.forename: Peter M G
authors.initials: PM
authors.lastname: Munro
authors.forename: Ricardo Micheler
authors.initials: RM
authors.lastname: Richardson
authors.forename: Maryse
authors.initials: M
authors.lastname: Bailly
authors.forename: Santa Jeremy
authors.initials: SJ
authors.lastname: Ono
mesh_terms: D000818:Animals; D015550:Cell Degranulation / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D019742:Chemokines, CC / Q000276:immunology; D004789:Enzyme Activation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008407:Mast Cells / Q000276:immunology* / Q000648:ultrastructure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology*; D017455:Receptors, IgE / Q000276:immunology*; D015398:Signal Transduction / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D054460:rho-Associated Kinases
chemical_list: C515300:CCR1 protein, human; C515302:Ccr1 protein, rat; D019742:Chemokines, CC; D047908:Intracellular Signaling Peptides and Proteins; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D017455:Receptors, IgE; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins