Sepsis, or septic shock, is an excessive inflammatory response to microbial components, particularly gram-negative bacterial lipopolysaccharide (LPS), that is a significant cause of morbidity and mortality worldwide. It is characterized by a massive release of proinflammatory cytokines that results in tissue damage, an uncontrolled reduction in blood pressure, multiple organ failure, and death. R&D Systems now offers new tools for sepsis research including components of the LPS receptor complex as well as TREM-1.
CD14 can exist as a soluble serum protein or a glycosylphosphatidyl inositol (GPI)-anchored cell surface protein expressed on monocytes/macrophages, dendritic cells and granulocytes. CD14 is a pattern recognition receptor that binds LPS and a variety of other ligands derived from microbial sources. The binding of CD14 with LPS is catalyzed by LPS-binding protein (LBP). CD14 then binds Toll-like Receptor 4 (TLR4) complexed with MD-2 to transduce LPS signals. This LPS receptor complex may also include other cell type-specific components such as complement receptors, heat shock proteins, chemokine receptors, and others.
Lipopolysaccharide Binding Protein (LBP) is a soluble glycoprotein synthesized mainly by hepatocytes and by pulmonary and gastrointestinal epithelial cells. LBP belongs to a family of lipid-binding proteins that includes bactericidal/permeability increasing protein (BPI), phospholipid ester transfer protein (PLTP), and cholesterol ester transfer protein (CETP). LBP binds the lipid A portion of LPS to catalyze the binding of LPS to CD14 and promote LPS-induced immune responses.
Toll-like Receptor 4 (TLR4) is a type I transmembrane protein that belongs to the expanding IL-1 R/TLR superfamily. It is a pattern recognition receptor and is expressed on many cell types including macrophages, dendritic cells, granulocytes, B cells, and T cells. The LPS-LBP-CD14 complex presents LPS to TLR4, activating inflammatory gene expression through NF-kB and MAPK signaling pathways. The secreted protein MD-2, as well as other cell-type specific integral membrane and extracellular proteins, form a complex with TLR4 and enhance LPS responsiveness.
Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) is a type I transmembrane orphan receptor of the immunoglobulin superfamily. It is expressed on monocytes, macrophages, dendritic cells, neutrophils, and natural killer cells. TREM-1 appears to be indirectly responsive to LPS as its expression is upregulated by LPS and its activation leads to LPS-like effects. Engagement of TREM-1 with a cross-linking monoclonal antibody leads to inflammatory cytokine expression and has been implicated as a mediator of sepsis. TREM-1 lacks known signaling motifs in its extremely short cytoplasmic domain and thus requires a separate signal transducing subunit, termed DAP12.