title: Evidence that integrin alpha IIb beta 3-dependent interaction of mast cells with fibrinogen exacerbates chronic inflammation.
abstract: Integrin alpha IIb beta 3 is expressed in mast cells as well as in megakaryocytes/platelets. A recent study has shown that surface expression levels of integrin alpha V beta 3 are elevated in integrin alpha IIb-deficient bone marrow-derived mast cells (BMMCs) as compared with wild-type (WT) counterparts, but the underlying mechanism remains obscure. Here we demonstrate by transducing integrin alpha IIb into integrin alpha IIb-deficient BMMCs that surface expression levels of integrin alpha V beta 3 are inversely related to those of integrin alpha IIb beta 3. Thus, competitive association of integrin beta 3 with integrin alpha IIb or integrin alpha V determines surface expression levels of integrin alpha IIb beta 3 or alpha V beta 3 in mast cells. We compared WT and integrin alpha IIb-deficient BMMCs as well as integrin alpha IIb-deficient BMMCs transduced with integrin alpha IIb(WT) or non-functional alpha IIb(D163A) mutant and found that enhancement of proliferation, degranulation, cytokine production, and migration of BMMCs through interaction with fibrinogen (FB) depended on integrin alpha IIb beta 3. In addition, elevated surface expression of integrin alpha V beta 3 failed to compensate for loss of FB-associated functions in integrin alpha IIb-deficient BMMCs while enhancing adhesion to vitronectin or von Willebrand factor. Importantly, integrin alpha IIb deficiency strongly suppressed chronic inflammation with the remarkable increase of mast cells induced by continuous intraperitoneal administration of FB, although it did not affect acute allergic responses or mast cell numbers in tissues in steady states. Interestingly, soluble FB promoted cytokine production of BMMCs in response to Staphylococcus aureus with FB-binding capacity, through integrin alpha IIb beta 3-dependent recognition of this pathogen. Collectively, integrin alpha IIb beta 3 in mast cells plays an important part in FB-associated, chronic inflammation and innate immune responses.
authors.affiliation: Division of Cellular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Oki
authors.forename: Koji
authors.initials: K
authors.lastname: Eto
authors.forename: Kumi
authors.initials: K
authors.lastname: Izawa
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yamanishi
authors.forename: Naoki
authors.initials: N
authors.lastname: Inagaki
authors.forename: Jon
authors.initials: J
authors.lastname: Frampton
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitamura
authors.forename: Jiro
authors.initials: J
authors.lastname: Kitaura
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005340:Fibrinogen / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005340:Fibrinogen