Ceramide Keeps Mast Cells in Check

Science Signaling  27 Nov 2012:
Vol. 5, Issue 252, pp. ec302
DOI: 10.1126/scisignal.2003810

Mast cells trigger allergic reactions in response to engagement of the high-affinity immunoglobulin E receptor (FcεRI) complex on the cell surface. FcεRI signaling depends on its immunoreceptor tyrosine-based activation motifs (ITAMs). Activated mast cells undergo degranulation and secrete vasoactive amines, such as histamine, and proinflammatory cytokines, including interleukin-6 (IL-6). Izawa et al. investigated a role for the receptor LMIR3, which contains inhibitory signaling motifs (ITIMs), in inhibiting signaling by FcεRI. Degranulation and cytokine release after stimulation of the FcεRI were similar in cultured bone marrow–derived mast cells (BMMCs) from wild-type and LMIR3-deficient mice; however, coengagement of FcεRI and LMIR3 resulted in decreased activation of wild-type cells. Mast cell–dependent airway inflammation and dermatitis were more severe in LMIR3-deficient mice than in wild-type mice, suggesting the presence of an LMIR3 ligand in the affected tissues. Experiments with a fusion protein containing the LMIR3 extracellular domain showed that the lipid ceramide bound to LMIR3. Ceramide inhibited FcεRI-dependent degranulation and IL-6 release by wild-type, but not LMIR3-deficient, BMMCs in vitro. Stimulation of wild-type BMMCs through FcεRI in the presence of ceramide led to tyrosine phosphorylation of LMIR3, colocalization of LMIR3 and FcεRI at the plasma membrane, and recruitment to LMIR3 of phosphatases that inhibit FcεRI signaling. When pretreated with liposomal ceramides, wild-type, but not LMIR3-deficient, mice exhibited decreased allergic responses compared to those in wild-type mice pretreated with control liposomes. Confocal microscopy showed that extracellular ceramide was present in mouse skin and that its abundance was increased in inflamed tissues. Together, these data suggest that the binding of extracellular ceramide to the mast cell receptor LMIR3 inhibits FcεRI signaling and decreases allergic responses in vivo.

K. Izawa, Y. Yamanishi, A. Maehara, M. Takahashi, M. Isobe, S. Ito, A. Kaitani, T. Matsukawa, T. Matsuoka, F. Nakahara, T. Oki, H. Kiyonari, T. Abe, K. Okumura, T. Kitamura, J. Kitaura, The receptor LMIR3 negatively regulates mast cell activation and allergic responses by binding to extracellular ceramide. Immunity 37, 827–839 (2012). [PubMed]