1. Lipopolysaccharide-Induced CD300b Receptor Binding to Toll-like Receptor 4 Alters Signaling to Drive Cytokine Responses that Enhance Septic Shock.
- Author
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Voss OH, Murakami Y, Pena MY, Lee HN, Tian L, Margulies DH, Street JM, Yuen PS, Qi CF, Krzewski K, and Coligan JE
- Subjects
- Adaptor Proteins, Vesicular Transport metabolism, Animals, HEK293 Cells, Humans, Interleukin-10 genetics, Lipopolysaccharides immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88 metabolism, NF-kappa B metabolism, Phosphatidylinositol 3-Kinases metabolism, Protein Binding, Receptors, Immunologic genetics, Signal Transduction, Syk Kinase metabolism, Toll-Like Receptor 4 metabolism, Interleukin-10 metabolism, Macrophages immunology, Peritonitis immunology, Receptors, Immunologic metabolism, Sepsis immunology
- Abstract
Receptor CD300b is implicated in regulating the immune response to bacterial infection by an unknown mechanism. Here, we identified CD300b as a lipopolysaccharide (LPS)-binding receptor and determined the mechanism underlying CD300b augmentation of septic shock. In vivo depletion and adoptive transfer studies identified CD300b-expressing macrophages as the key cell type augmenting sepsis. We showed that CD300b, and its adaptor DAP12, associated with Toll-like receptor 4 (TLR4) upon LPS binding, thereby enhancing TLR4-adaptor MyD88- and TRIF-dependent signaling that resulted in an elevated pro-inflammatory cytokine storm. LPS engagement of the CD300b-TLR4 complex led to the recruitment and activation of spleen tyrosine kinase (Syk) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). This resulted in an inhibition of the ERK1/2 protein kinase- and NF-κB transcription factor-mediated signaling pathways, which subsequently led to a reduced interleukin-10 (IL-10) production. Collectively, our data describe a mechanism of TLR4 signaling regulated by CD300b in myeloid cells in response to LPS., (Published by Elsevier Inc.)
- Published
- 2016
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