TY - JOUR
T1 - SIRPα/CD172α regulates eosinophil homeostasis
AU - Garcia, Noel Verjan
AU - Umemoto, Eiji
AU - Saito, Yasuyuki
AU - Yamasaki, Mikako
AU - Hata, Erina
AU - Matozaki, Takashi
AU - Murakami, Masaaki
AU - Jung, Yun Jae
AU - Woo, So Youn
AU - Seoh, Ju Young
AU - Jang, Myoung Ho
AU - Aozasa, Katsuyuki
AU - Miyasaka, Masayuki
PY - 2011/9/1
Y1 - 2011/9/1
N2 - 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 SIRPa 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.
AB - 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 SIRPa 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.
UR - http://www.scopus.com/inward/record.url?scp=80052688904&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1101008
DO - 10.4049/jimmunol.1101008
M3 - Article
C2 - 21775684
AN - SCOPUS:80052688904
SN - 0022-1767
VL - 187
SP - 2268
EP - 2277
JO - Journal of Immunology
JF - Journal of Immunology
IS - 5
ER -