title: Cutting Edge: Ezrin Regulates Inflammation by Limiting B Cell IL-10 Production.
abstract: IL-10 produced by B cells is important for controlling inflammation, thus underscoring the need to identify mechanisms regulating its production. In this study, we demonstrate that conditional deletion of ezrin in B cells increases IL-10 production induced by TLR4 ligation. The MyD88-independent Toll/IL-1R domain-containing adapter inducing IFN-β-IFN regulatory factor 3 pathway is required for Ezrin-deficient B cells to produce higher IL-10 upon LPS stimulation. Treatment of B cells with a novel small-molecule inhibitor of ezrin induces its dephosphorylation and increases LPS-induced NF-κB and IFN regulatory factor 3 activation and IL-10 secretion, indicating a role for threonine 567 phosphorylation of ezrin in limiting IL-10. Loss of ezrin in B cells results in dampened proinflammatory response to a sublethal dose of LPS in vivo, which is dependent on increased IL-10 production. Taken together, our data yield new insights into molecular and membrane-cytoskeletal regulation of B cell IL-10 production and reveal ezrin as a potential therapeutic target in inflammatory diseases.
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Debasis
authors.initials: D
authors.lastname: Pore
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Ken
authors.initials: K
authors.lastname: Matsui
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Neetha
authors.initials: N
authors.lastname: Parameswaran
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195 guptan@ccf.org.
authors.forename: Neetu
authors.initials: N
authors.lastname: Gupta
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000276:immunology*; D005434:Flow Cytometry; D015151:Immunoblotting; D007249:Inflammation / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D016753:Interleukin-10; D000099149:Ezrin; C556062:IL10 protein, mouse