title: SIRPα/CD172a regulates eosinophil homeostasis.
abstract: Eosinophils are abundant in the lamina propria of the small intestine, but they rarely show degranulation in situ under steady-state conditions. In this study, using two novel mAbs, we found that intestinal eosinophils constitutively expressed a high level of an inhibitory receptor signal regulatory protein α (SIRPα)/CD172a and a low, but significant, level of a tetraspanin CD63, whose upregulation is closely associated with degranulation. Cross-linking SIRPα/CD172a on the surface of wild-type eosinophils significantly inhibited the release of eosinophil peroxidase induced by the calcium ionophore A23187, whereas this cross-linking effect was not observed in eosinophils isolated from mice expressing a mutated SIRPα/CD172a that lacks most of its cytoplasmic domain (SIRPα Cyto(-/-)). The SIRPα Cyto(-/-) eosinophils showed reduced viability, increased CD63 expression, and increased eosinophil peroxidase release with or without A23187 stimulation in vitro. In addition, SIRPα Cyto(-/-) mice showed increased frequencies of Annexin V-binding eosinophils and free MBP(+)CD63(+) extracellular granules, as well as increased tissue remodeling in the small intestine under steady-state conditions. Mice deficient in CD47, which is a ligand for SIRPα/CD172a, recapitulated these phenomena. Moreover, during Th2-biased inflammation, increased eosinophil cell death and degranulation were obvious in a number of tissues, including the small intestine, in the SIRPα Cyto(-/-) mice compared with wild-type mice. Collectively, our results indicated that SIRPα/CD172a regulates eosinophil homeostasis, probably by interacting with CD47, with substantial effects on eosinophil survival. Thus, SIRPα/CD172a is a potential therapeutic target for eosinophil-associated diseases.
authors.affiliation: Laboratory of Immunodynamics, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
authors.forename: Noel
authors.initials: N
authors.lastname: Verjan Garcia
authors.forename: Eiji
authors.initials: E
authors.lastname: Umemoto
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Saito
authors.forename: Mikako
authors.initials: M
authors.lastname: Yamasaki
authors.forename: Erina
authors.initials: E
authors.lastname: Hata
authors.forename: Takashi
authors.initials: T
authors.lastname: Matozaki
authors.forename: Masaaki
authors.initials: M
authors.lastname: Murakami
authors.forename: Yun-Jae
authors.initials: YJ
authors.lastname: Jung
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Woo
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Seoh
authors.forename: Myoung Ho
authors.initials: MH
authors.lastname: Jang
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Aozasa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyasaka
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D051928:CD47 Antigen / Q000276:immunology / Q000378:metabolism; D015550:Cell Degranulation / Q000276:immunology; D002469:Cell Separation; D002853:Chromatography, Liquid; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006706:Homeostasis / Q000276:immunology*; D018928:Immunity, Mucosal / Q000276:immunology; D047468:Immunoprecipitation; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010980:Platelet Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology* / Q000378:metabolism; D060149:Tetraspanin 30
chemical_list: D015703:Antigens, CD; D051928:CD47 Antigen; C554587:Cd63 protein, mouse; D010980:Platelet Membrane Glycoproteins; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; D060149:Tetraspanin 30