Atopy Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Division of Cellular Therapy/Division of Stem Cell Signaling, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
Sci Rep. 2017 Jun 27;7(1):4298. doi: 10.1038/s41598-017-04647-z.
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.
脓毒症是一种严重的临床问题。先天免疫的负调控与脓毒症的进展有关，但潜在的机制尚不清楚。在这里，我们表明受体 CD300f 促进脓毒症的疾病进展。在盲肠结扎和穿刺 (CLP) 后，CD300f 小鼠（一种脓毒性腹膜炎的小鼠模型）免受死亡的影响。CD300f 在肥大细胞中高度表达，并募集中性粒细胞到腹腔中。对接受野生型或 CD300f 肥大细胞或中性粒细胞移植的小鼠进行分析表明，CD300f 缺陷不影响中性粒细胞的固有迁移能力，但增强了 CLP 操作小鼠腹腔中中性粒细胞趋化因子的产生（来自肥大细胞和中性粒细胞），导致大量中性粒细胞有效清除大肠杆菌。神经酰胺-CD300f 相互作用抑制了大肠杆菌刺激的肥大细胞和中性粒细胞中中性粒细胞趋化因子的释放。破坏神经酰胺-CD300f 相互作用的试剂的给药通过刺激中性粒细胞募集来预防 CLP 诱导的脓毒症，而含有神经酰胺的囊泡的给药则加重了脓毒症。CLP 后，腹腔中神经酰胺的细胞外浓度增加，这表明细胞外神经酰胺、CD300f 配体可能在先天免疫反应的负反馈抑制中发挥作用。因此，CD300f 是治疗脓毒症的一个有吸引力的靶点。
