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

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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. Host defense against gram-negative bacteria is facilitated by LPS recognition by TLR4-expressing immune cells, primarily macrophages. Coligan and colleagues identify CD300b as an LPS binding receptor and show that during acute infection (septic shock), CD300b-TLR4 complex formation regulates both TLR4-MyD88- and TLR4-TRIF-meditated signaling responses in macrophages, thereby augmenting lethal inflammation.

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Voss, O. H., Murakami, Y., Pena, M. Y., Lee, H. N., Tian, L., Margulies, D. H., … Coligan, J. E. (2016). Lipopolysaccharide-Induced CD300b Receptor Binding to Toll-like Receptor 4 Alters Signaling to Drive Cytokine Responses that Enhance Septic Shock. Immunity, 44(6), 1365–1378. https://doi.org/10.1016/j.immuni.2016.05.005

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