Ceramide-CD300f Binding Inhibits Lipopolysaccharide-induced Skin Inflammation.
Ceramide-CD300f Binding Inhibits Lipopolysaccharide-induced Skin Inflammation.
复制标题
DOI：
10.1074/jbc.m116.768366
复制
发表时间：
2017-02-17
期刊：
影响因子：
--
通讯作者：
Kitaura J
中科院分区：
文献类型：
--
作者：
Shiba E;Izawa K;Kaitani A;Isobe M;Maehara A;Uchida K;Maeda K;Nakano N;Ogawa H;Okumura K;Kitamura T;Shimizu T;Kitaura J
LPS触发炎症反应;然而，体内LPS反应的负调控仍然知之甚少。CD 300 f是成对的活化和抑制受体的CD 300家族中的抑制性受体。我们先前已经确定神经酰胺作为CD 300 f的配体，并表明神经酰胺与CD 300 f的结合抑制小鼠模型中IgE介导的肥大细胞活化和过敏反应。在这里，我们确定了CD 300 f在抑制LPS诱导的皮肤炎症中的关键作用。CD 300 f缺陷显著增强LPS诱导的小鼠皮肤水肿和中性粒细胞募集。与野生型小鼠相比，在注射LPS的CD 300 f −/−小鼠的皮袋渗出物中检测到更高水平的增加血管通透性的因子和诱导中性粒细胞募集的因子。CD 300 f在肥大细胞和募集的中性粒细胞中高度表达，但在皮肤骨髓细胞中的巨噬细胞中不表达。CD 300 f缺陷不能影响中性粒细胞的内在迁移能力。神经酰胺-CD 300 f结合抑制肥大细胞和中性粒细胞对LPS的反应释放化学介质。连续转移实验表明，肥大细胞介导了LPS刺激的CD 300 f −/−小鼠皮肤水肿的增强，而肥大细胞与募集的中性粒细胞一起介导了中性粒细胞的大量蓄积。重要的是，施用神经酰胺抗体或含神经酰胺的囊泡分别增强或抑制野生型小鼠的LPS诱导的皮肤炎症。因此，神经酰胺-CD 300 f结合抑制LPS诱导的皮肤炎症，暗示CD 300 f是体内Toll样受体4（TLR 4）信号传导的负调节剂。
LPS triggers inflammatory responses; however, the negative regulation of LPS responses in vivo remains poorly understood. CD300f is an inhibitory receptor among the CD300 family of paired activating and inhibitory receptors. We have previously identified ceramide as a ligand for CD300f and shown that the binding of ceramide to CD300f inhibits IgE-mediated mast cell activation and allergic responses in mouse models. Here we identify the critical role of CD300f in inhibiting LPS-induced skin inflammation. CD300f deficiency remarkably enhanced LPS-induced skin edema and neutrophil recruitment in mice. Higher levels of factors that increase vascular permeability and of factors that induce neutrophil recruitment were detected in LPS-injected skin pouch exudates of CD300f−/− mice as compared with wild-type mice. CD300f was highly expressed in mast cells and recruited neutrophils, but not in macrophages, among skin myeloid cells. CD300f deficiency failed to influence the intrinsic migratory ability of neutrophils. Ceramide-CD300f binding suppressed the release of chemical mediators from mast cells and from neutrophils in response to LPS. Adoptive transfer experiments indicated that mast cells mediated enhanced edema in LPS-stimulated skin of CD300f−/− mice, whereas mast cells together with recruited neutrophils mediated robust neutrophil accumulation. Importantly, administering a ceramide antibody or ceramide-containing vesicles enhanced or suppressed LPS-induced skin inflammation of wild-type mice, respectively. Thus, ceramide-CD300f binding inhibits LPS-induced skin inflammation, implicating CD300f as a negative regulator of Toll-like receptor 4 (TLR4) signaling in vivo.