| First Author | Sharma N | Year | 2019 |
| Journal | Front Immunol | Volume | 10 |
| Pages | 1020 | PubMed ID | 31156621 |
| Mgi Jnum | J:294984 | Mgi Id | MGI:6458254 |
| Doi | 10.3389/fimmu.2019.01020 | Citation | Sharma N, et al. (2019) SLAP Is a Negative Regulator of FcepsilonRI Receptor-Mediated Signaling and Allergic Response. Front Immunol 10:1020 |
| abstractText | Binding of antigen to IgE-high affinity FcepsilonRI complexes on mast cells and basophils results in the release of preformed mediators such as histamine and de novo synthesis of cytokines causing allergic reactions. Src-like adapter protein (SLAP) functions co-operatively with c-Cbl to negatively regulate signaling downstream of the T cell receptor, B cell receptor, and receptor tyrosine kinases (RTK). Here, we investigated the role of SLAP in FcepsilonRI-mediated mast cell signaling, using bone marrow derived mast cells (BMMCs) from SLAP knock out (SLAP KO) mice. Mature SLAP-KO BMMCs displayed significantly enhanced antigen induced degranulation and synthesis of IL-6, TNFalpha, and MCP-1 compared to wild type (WT) BMMCs. In addition, SLAP KO mice displayed an enhanced passive cutaneous anaphylaxis response. In agreement with a negative regulatory role, SLAP KO BMMCs showed enhanced FcepsilonRI-mediated signaling to downstream effector kinases, Syk, Erk, and Akt. Recombinant GST-SLAP protein binds to the FcepsilonRIbeta chain and to the Cbl-b in mast cell lysates, suggesting a role in FcepsilonRI down regulation. In addition, the ubiquitination of FcepsilonRIgamma chain and antigen mediated down regulation of FcepsilonRI is impaired in SLAP KO BMMCs compared to the wild type. In line with these findings, stimulation of peripheral blood human basophils with FcepsilonRIalpha antibody, or a clinically relevant allergen, resulted in increased SLAP expression. Together, these results indicate that SLAP is a dynamic regulator of IgE-FcepsilonRI signaling, limiting allergic responses. |
