Recognition and plasma clearance of endotoxin by scavenger receptors

Abstract

Lipid A is the active moiety of lipopolysaccharide (LPS, also referred to as endotoxin), a surface component of Gram-negative bacteria that stimulates macrophage activation and causes endotoxic shock. Macrophages can bind, internalize and partially degrade LPS, lipid A and its bioactive precursor, lipid IVA. We report here that lipid IVA binding and subsequent metabolism to a less active form by macrophage-like RAW 264.7 cells is mediated by the macrophage scavenger receptor. Scavenger-receptor ligands inhibit lipid IVA binding to, and metabolism by, RAW cells, and lipid IVA binds to type I and type II bovine scavenger receptors on transfected Chinese hamster ovary cells. Although in vitro competition studies with RAW cells indicate that scavenger receptor binding is not involved in LPS or lipid IVA-induced stimulation of macrophages, in vivo studies show that scavenger-receptor ligands greatly inhibit hepatic uptake of lipid IVA in mice. Thus, scavenger receptors expressed on macrophages may have an important role in the clearance and detoxification of endotoxin in animals.

Toll-Like Receptors in Health and Disease: Complex Questions Remain

“…Scavenger receptor-A (SR-A) and macrophage receptor with collagen structure each bind and are regulated by LPS (16,17), and participate in microbial recognition leading to phagocytosis (16,18). Scavenger receptors may also modulate TLR4-mediated responses to LPS, since SR-A-mediated internalization of LPS leads to its degradation but does not induce cellular activation (19), and SR-A knockout mice are more sensitive to endotoxemia (20). Finally, by analogy with signaling of Drosophila Toll where, in response to infection, proteases generate a true TLR ligand, there is some evidence for protease-dependent signaling in human TLR4 responses (21,22), suggesting that LPS signaling may involve complex cell surface events.…”

De novo expression of the class-A macrophage scavenger receptor conferring resistance to apoptosis in differentiated human THP-1 monocytic cells

“…1,2 The MSR-mediated uptake of modified LDL promotes intracellular accumulation of lipids, particularly cholesterol and cholesteryl esters, leading to the transformation of macrophages or other MSR-bearing cells into lipidladen foam cells in atherosclerosis, an arterial disease that can cause cardiac and cerebral infarction. In addition to the modified lipoproteins, MSR recognizes and binds other macromolecules with clustered negative charges, including the bacterial product lipopolysaccharide or endotoxin 3 and certain polyanionic compounds. 4 The clearance of bacterial products mediated by the class-A MSR plays an important role in protecting the host against lethal endotoxin shock.…”

Scavenger receptor class A type I/II (CD204) null mice fail to develop fibrosis following silica exposure

“…Other naturally occurring ligands include polynucleotides and polysaccharides, gram-positive and gram-negative bacteria, and apoptotic cells (16,53,67). The versatile biological functions of SR include the clearance of pathological substances, host defense, cell adhesion, activation of intracellular signaling events, and cytokine production (21,26,50,51,57,65), although it is not yet clear how SR coordinate these immune and homeostatic functions.…”