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Lipopolysaccharide-induced binding of receptor CD300b to Toll-like receptor 4 alters signaling to drive lethal cytokine responses that enhance septic shock
- Publication Year :
- 2016
-
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.
- Subjects :
- Lipopolysaccharides
Mice, Knockout
Macrophages
NF-kappa B
Peritonitis
Article
Interleukin-10
Mice, Inbred C57BL
Toll-Like Receptor 4
Adaptor Proteins, Vesicular Transport
Mice
Phosphatidylinositol 3-Kinases
HEK293 Cells
Sepsis
Myeloid Differentiation Factor 88
Animals
Humans
Syk Kinase
Receptors, Immunologic
Protein Binding
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.pmid..........3caf383cfb8159fd6dcd5ab72df237c6