Role of CD14 in human disease

Abstract

The cell surface antigen CD14 is primarily understood to act as a co-receptor for toll-like receptors (TLRs) to activate innate immunity responses to pathogens and tissue injury in macrophages and monocytes. However, roles for CD14 are increasingly being uncovered in disease responses in epithelial and endothelial cells. Consistent with these broader functions, CD14 expression is altered in a variety of non-immune cell types in response to a several of disease states. Moreover, soluble CD14 activated by factors from both pathogens and tissue damage may initiate signalling in a variety of non-immune cells. This review examined the current understanding CD14 in innate immunity as well as its potential functions in nonimmune cells and associated human diseases.

Keywords: CD14; LPS; human disease; immunity; inflammation; metabolism; organ injury.

Figure1:. CD14 activates multiple signaling pathways.

a) In both human and mouse dendritic cells, CD14-LPS complex initiates TLR4-independent NFAT activation in a variety of inflammatory cell types. CD14 localizes to lipid rafts and directly recruits Src family kinase (SFK) and phospholipase C$\gamma$2 (PLC$\gamma$2). Subsequent dephosphorylation of NFAT promotes its translocation into the nucleus where it drives pro-apoptotic gene expression, thus enabling self-tolerance. b) LBP-dependent combination of the CD14-LPS complex with TLR4-MD-2 in lipid rafts promotes TIRAP-MyD88 to bind to the TIR domains of TLR4. The newly formed “myddosome” triggers the activation of NF-$\kappa$B and MAPK through the TNF-receptor associated factor (TRAF). Consequently, numerous proinflammatory cytokines such as TNF-$\alpha$, IL-1$\beta$, and IL-6 are secreted. c) LPS bound CD14 activates ITAM-containing adaptor proteins that stimulate the tyrosine kinase Syk and PLC$\gamma$2 to initiate the delivery of the TLR4/MD2 complex from the plasma membrane to endosomal compartments. d) In endosomal vesicles, CD14 further enables LPS to stimulate the TRAM-TRIF pathway to illicit interferon-3 regulatory factor (IRF3) production and subsequent type-1 IFN production. e) In human monocytes, epithelial cells and keratinocytes, when CD14 binds to LPS during tissue damage, its endocytosis allows it to bind and activate the inflammasome assembly independently of TLRs. CD14 activates the NLRP3-mediated inflammasome assembly that results in the release of IL-1$\beta$ and Il-18 with or without cell death.