Signal regulatory protein α negatively regulates mast-cell activation following FcεRI aggregation

Authors

  • Yu-fei Pan,

    1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, P. R. China
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    • These authors contributed equally to this work.

  • Li-wei Dong,

    1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, P. R. China
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    • These authors contributed equally to this work.

  • Min Wang,

    1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, P. R. China
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    • These authors contributed equally to this work.

  • Guang-zhen Yang,

    1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, P. R. China
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  • Jian Zhang,

    1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, P. R. China
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  • Shuang-xi Li,

    1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, P. R. China
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  • Bo Zhang,

    1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, P. R. China
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  • Chun Yang,

    1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, P. R. China
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  • Zhong Li,

    1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, P. R. China
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  • Ye-xiong Tan,

    Corresponding author
    • International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, P. R. China
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  • Hong-yang Wang

    Corresponding author
    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
    • International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, P. R. China
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Full correspondence: Dr. Hong-yang Wang, International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, 225 Changhai Road, Shanghai 200438, China

Fax: +86-2165566851

e-mail: hywangk@vip.sina.com

Additional correspondence: Dr. Ye-xiong Tan, International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, 225 Changhai Road, Shanghai 200438, China. e-mail: yxtan1214@yahoo.com.cn

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.

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