Abstract

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.

Highlights

  • The CD300, known as leukocyte mono-immunoglobulin-like receptor (LMIR), CMRF35-like molecule (CLM), or myeloid-associated immunoglobulin-like receptor (MAIR), members modulate immune cell responses via their paired activating and inhibitory receptor functions [1,2,3,4,5,6,7]

  • LPS-induced Skin Inflammation Was Profoundly Enhanced in CD300fϪ/Ϫ Mice as Compared with WT Mice—LPS was intradermally injected into the ears of WT or CD300fϪ/Ϫ mice

  • Vascular permeability was enhanced in KitW-sh/W-sh mice transplanted with CD300fϪ/Ϫ bone marrow-derived mast cell (BMMC), transduced to express CD300f-Y241F/Y289F/Y325F, at levels comparable with those of KitW-sh/W-sh mice transplanted with CD300f-deficient BMMC (Fig. 3, D and E) [9, 10], indicating the critical importance of the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based switch motif (ITSM) to LPS-induced skin edema

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Summary

Introduction

The CD300, known as leukocyte mono-immunoglobulin-like receptor (LMIR), CMRF35-like molecule (CLM), or myeloid-associated immunoglobulin-like receptor (MAIR), members modulate immune cell responses via their paired activating and inhibitory receptor functions [1,2,3,4,5,6,7]. Vascular permeability was enhanced in KitW-sh/W-sh mice transplanted with CD300fϪ/Ϫ BMMC, transduced to express CD300f-Y241F/Y289F/Y325F, at levels comparable with those of KitW-sh/W-sh mice transplanted with CD300f-deficient BMMC (Fig. 3, D and E) [9, 10], indicating the critical importance of the ITIM and ITSM to LPS-induced skin edema.

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