Disrupting ceramide-CD300f interaction prevents septic peritonitis by stimulating neutrophil recruitment.
Disrupting ceramide-CD300f interaction prevents septic peritonitis by stimulating neutrophil recruitment.
复制标题
DOI：
10.1038/s41598-017-04647-z
复制
发表时间：
2017-06-27
影响因子：
4.6
通讯作者：
Kitaura J
中科院分区：
文献类型：
--
作者：
Izawa K;Maehara A;Isobe M;Yasuda Y;Urai M;Hoshino Y;Ueno K;Matsukawa T;Takahashi M;Kaitani A;Shiba E;Takamori A;Uchida S;Uchida K;Maeda K;Nakano N;Yamanishi Y;Oki T;Voehringer D;Roers A;Nakae S;Ishikawa J;Kinjo Y;Shimizu T;Ogawa H;Okumura K;Kitamura T;Kitaura J
脓毒症是一个严重的临床问题。先天免疫的负调节与脓毒症进展相关，但其潜在机制仍不清楚。在这里，我们表明，受体CD 300 f促进脓毒症的疾病进展。CD 300 f −/−小鼠在盲肠结扎和穿孔（CLP）后免于死亡，这是一种脓毒性腹膜炎的小鼠模型。CD 300 f在肥大细胞中高度表达，并在腹腔中招募中性粒细胞。小鼠的分析（例如，肥大细胞缺陷小鼠）接受野生型或CD 300 f −/−肥大细胞或中性粒细胞的移植，表明CD 300 f缺陷不影响中性粒细胞的内在迁移能力，但增强了CLP手术小鼠腹腔中中性粒细胞化学引诱物的产生（来自肥大细胞和中性粒细胞），导致中性粒细胞的大量积累，从而有效消除大肠杆菌。神经酰胺-CD 300 f相互作用抑制大肠杆菌刺激的肥大细胞和中性粒细胞释放中性粒细胞趋化因子。给予破坏神经酰胺-CD 300 f相互作用的试剂通过刺激中性粒细胞募集来预防CLP诱导的脓毒症，而含神经酰胺的囊泡则加重脓毒症。CLP后腹膜腔中神经酰胺的细胞外浓度增加，表明细胞外神经酰胺、CD 300 f配体在先天性免疫应答的负反馈抑制中可能发挥作用。因此，CD 300 f是治疗脓毒症的有吸引力的靶点。
Sepsis is a serious clinical problem. Negative regulation of innate immunity is associated with sepsis progression, but the underlying mechanisms remains unclear. Here we show that the receptor CD300f promotes disease progression in sepsis. CD300f −/− mice were protected from death after cecal ligation and puncture (CLP), a murine model of septic peritonitis. CD300f was highly expressed in mast cells and recruited neutrophils in the peritoneal cavity. Analysis of mice (e.g., mast cell-deficient mice) receiving transplants of wild-type or CD300f −/− mast cells or neutrophils indicated that CD300f deficiency did not influence intrinsic migratory abilities of neutrophils, but enhanced neutrophil chemoattractant production (from mast cells and neutrophils) in the peritoneal cavity of CLP-operated mice, leading to robust accumulation of neutrophils which efficiently eliminated Escherichia coli. Ceramide-CD300f interaction suppressed the release of neutrophil chemoattractants from Escherichia coli-stimulated mast cells and neutrophils. Administration of the reagents that disrupted the ceramide-CD300f interaction prevented CLP-induced sepsis by stimulating neutrophil recruitment, whereas that of ceramide-containing vesicles aggravated sepsis. Extracellular concentrations of ceramides increased in the peritoneal cavity after CLP, suggesting a possible role of extracellular ceramides, CD300f ligands, in the negative-feedback suppression of innate immune responses. Thus, CD300f is an attractive target for the treatment of sepsis.