Mutation of tyrosine 145 of lymphocyte cytosolic protein 2 protects mice from anaphylaxis and arthritis

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:124

Article

Lenox, Laurie E.^1,2  Kambayashi, Taku^2,3  Okumura, Mariko^2,3  Prieto, Christopher^1,2  Sauer, Karsten⁵  Bunte, Ralph M.⁶  Jordan, Martha S.^2,3  Koretzky, Gary A.^2,3,4  Nichols, Kim E.^1,2 

[1] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA

[2] Univ Penn, Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA

[3] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[4] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA

[5] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA USA

[6] Univ Penn, Univ Lab Anim Resources, Philadelphia, PA 19104 USA

关键词: Mast cells;    neutrophils;    Fc receptors;    integrins;    signal transduction;    SLP-76;    passive systemic anaphylaxis;    localized Shwartzman reaction;    arthritis;   

DOI  :  10.1016/j.jaci.2009.08.038

来源: Elsevier

【 摘 要 】

Background: Lymphocyte cytosolic protein 2, also known as Sire homology 2 domain-containing leukocyte phosphoprotein of 76 kilodaltons (SLP-76), is an essential adaptor molecule in myeloid cells, where it regulates Fc is an element of RI-induced mast cell (MC) and Fc gamma R- and integrin-induced neutrophil (polymorphonuclear leukocyte [PMN]) functions. SLP-76 contains 3 N-terminal tyrosines at residues 112, 128, and 145 that together are critical for its function. Objective: We sought to explore the relative importance of tyrosines 112, 128, and 145 of SLP-76 during MC and PMN activation. Methods: We examined in vitro MC and PMN functions using cells isolated from knock-in mice harboring phenylalanine substitution mutations at tyrosines 112 and 128 (Y112/128F) or 145 (Y145F). We also examined the effects of these mutations on in vivo MC and PMN activation using models of anaphylaxis, dermal inflammation, and serum-induced arthritis. Results: Mutations at Y112/Y128 and Y145 both interfered with SLP-76 activity; however, Y145F had a greater effect than Y112/128F on most in vitro FcR-induced functions. In vitro functional defects were recapitulated in vivo, where mice expressing Y145F exhibited greater attenuation of MC-dependent passive systemic anaphylaxis and PMN-mediated inflammatory responses. Notably, the Y145F mutation completely protected mice against development of joint-specific inflammation in the MC and PMN-dependent K/B x N model of arthritis. Conclusion: Our data indicate that Y145 is the most critical tyrosine supporting SLP-76 function in myeloid cells. Future efforts to dissect how Y145 mediates SLP-76-dependent signaling in MCs and PMNs will increase our understanding of these lineages and provide insights into the treatment of allergy and inflammation. (J Allergy Clin Immunol 2009;124:1088-98.)

【 授权许可】

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