title: The receptor LMIR3 negatively regulates mast cell activation and allergic responses by binding to extracellular ceramide.
abstract: Mast cells (MCs) are key effector cells in allergic reactions. However, the inhibitory mechanism that prevents excessive activation of MCs remains elusive. Here we show that leukocyte mono-immunoglobulin-like receptor 3 (LMIR3; also called CD300f) is a negative regulator of MC activation in vivo. LMIR3 deficiency exacerbated MC-dependent allergic responses in mice, including anaphylaxis, airway inflammation, and dermatitis. Both physical binding and functional reporter assays via an extracellular domain of LMIR3 showed that several extracellular lipids (including ceramide) and lipoproteins were possible ligands for LMIR3. Importantly, MCs were frequently surrounded by extracellular ceramide in vivo. Upon engagement of high-affinity immunoglobulin E receptor, extracellular ceramide-LMIR3 binding inhibited MC activation via immunoreceptor tyrosine-based inhibitory and switch motifs of LMIR3. Moreover, pretreatment with LMIR3-Fc fusion protein or antibody against either ceramide or LMIR3 interfered with this binding in vivo, thereby exacerbating passive cutaneous anaphylaxis. Thus, the interaction between extracellular ceramide and LMIR3 suppressed MC-dependent allergic responses.
authors.affiliation: Division of Cellular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Izawa
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yamanishi
authors.forename: Akie
authors.initials: A
authors.lastname: Maehara
authors.forename: Mariko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Masamichi
authors.initials: M
authors.lastname: Isobe
authors.forename: Shinichi
authors.initials: S
authors.lastname: Ito
authors.forename: Ayako
authors.initials: A
authors.lastname: Kaitani
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Matsukawa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsuoka
authors.forename: Fumio
authors.initials: F
authors.lastname: Nakahara
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Oki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyonari
authors.forename: Takaya
authors.initials: T
authors.lastname: Abe
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitamura
authors.forename: Jiro
authors.initials: J
authors.lastname: Kitaura
mesh_terms: D000707:Anaphylaxis / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002518:Ceramides / Q000276:immunology* / Q000378:metabolism*; D003872:Dermatitis / Q000276:immunology / Q000378:metabolism; D006967:Hypersensitivity / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007073:Immunoglobulin E / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008074:Lipoproteins / Q000276:immunology / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology* / Q000378:metabolism*; D014443:Tyrosine / Q000276:immunology / Q000378:metabolism
chemical_list: C482560:CLM-1 protein, mouse; D002518:Ceramides; D008074:Lipoproteins; D017455:Receptors, IgE; D011971:Receptors, Immunologic; D007073:Immunoglobulin E; D014443:Tyrosine