title: Signal regulatory protein α negatively regulates mast-cell activation following FcεRI aggregation.
abstract: Mast cells elicit allergic reaction through degranulation and release of proinflammatory mediators after aggregation of the IgE receptor FcεRI. Here we provide evidence to show that signal regulatory protein α (SIRPα), an ITIM-containing receptor, is an endogenous regulator of IgE-Ag induced mast-cell activation. SIRPα expression is promptly reduced in mast cells in response to FcεRI aggregation. Impaired expression of SIRPα in mast cells facilitates FcεRI-evoked degranulation and de novo synthesis of cytokines (IL-4, IL-13, IL-6, and TNF-α). We further demonstrate that SIRPα knockdown in mast cells accelerates calcium mobilization and affects cytoskeletal rearrangement (F-actin disassembly and polymeric tubulin formation) after FcεRI aggregation. Mechanistic studies highlight the prolonged activation of NF-κB and MAPKs as well as PLC-γ after FcεRI stimulation as a consequence of the inhibition of SIRPα expression in mast cells. Immunoprecipitation analysis shows that SIRPα knockdown markedly increases IgE-induced SHP2 interaction with PI3K regulatory subunit PI3Kp85 or IKK-β in mast cells, indicating that SIRPα may accomplish this through its association and sequestration of SHP2. Collectively, our results strongly indicate that SIRPα is a biological important regulator of FcεRI signaling.
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, PR China.
authors.forename: Yu-fei
authors.initials: YF
authors.lastname: Pan
authors.forename: Li-wei
authors.initials: LW
authors.lastname: Dong
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Guang-zhen
authors.initials: GZ
authors.lastname: Yang
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Shuang-xi
authors.initials: SX
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
authors.forename: Ye-xiong
authors.initials: YX
authors.lastname: Tan
authors.forename: Hong-yang
authors.initials: HY
authors.lastname: Wang
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000235:genetics; D015550:Cell Degranulation / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003599:Cytoskeleton / Q000235:genetics; D007073:Immunoglobulin E / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011940:Receptor Aggregation; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; C501922:Sirpa protein, mouse; D034741:RNA, Small Interfering; D017455:Receptors, IgE; D011971:Receptors, Immunologic; D007073:Immunoglobulin E; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse; D051966:Phospholipase C gamma