Abstract
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.
Highlights
Lower counts of E. coli as well as remarkably lower levels of the proinflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 were found in both peritoneal lavage fluid (PLF) and peripheral blood (PB) collected 24 h after cecal ligation and puncture (CLP) in CD300f−/− mice compared with WT mice (Fig. 1d,e)
The vascular spread of E. coli and the concomitant hyper-inflammatory responses were prevented in CD300f−/− mice as early as 24 h after CLP, indicating that CD300f−/− mice were highly resistant to CLP-induced sepsis
A striking feature of CD300f−/− mice subjected to CLP is the dramatically enhanced accumulation of neutrophils after elevated production of neutrophil chemoattractants (e.g., MIP2, KC, and LTB4) and vascular permeabilityand inflammation-inducing factors in the peritoneal cavity, where feces-derived bacteria (e.g., E. coli) evoked inflammation
Summary
To identify the cell populations responsible for the enhanced neutrophil accumulation in CLP-operated CD300f−/− mice, we examined CD300f expression in peritoneal myeloid cells of WT mice. Transfusion of 107 neutrophils, irrespective of the expression of CD300f, improved survival of the CLP-operated mice (Supplementary Fig. S5), suggesting that an adequate number of recruited neutrophils can prevent CLP-induced sepsis.
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