Lipopolysaccharide-Induced CD300b Receptor Binding to Toll-like Receptor 4 Alters Signaling to Drive Cytokine Responses that Enhance Septic Shock

Immunity. 2016 Jun 21;44(6):1365-78. doi: 10.1016/j.immuni.2016.05.005. Epub 2016 May 31.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • HEK293 Cells
  • Humans
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism*
  • Lipopolysaccharides / immunology
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / metabolism
  • NF-kappa B / metabolism
  • Peritonitis / immunology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Binding
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Sepsis / immunology*
  • Signal Transduction
  • Syk Kinase / metabolism
  • Toll-Like Receptor 4 / metabolism


  • Adaptor Proteins, Vesicular Transport
  • LMIR5 protein, mouse
  • Lipopolysaccharides
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Receptors, Immunologic
  • TICAM-1 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Interleukin-10
  • Phosphatidylinositol 3-Kinases
  • Syk Kinase