Diverse pro-inflammatory endotoxin recognition systems of mammalian innate immunity [version 1; referees: 2 approved]

Abstract

In humans and other mammals, recognition of endotoxins—abundant surface lipopolysaccharides (LPS) of Gram-negative bacteria—provides a potent stimulus for induction of inflammation and mobilization of host defenses. The structurally unique lipid A region of LPS is the principal determinant of this pro-inflammatory activity. This region of LPS is normally buried within the bacterial outer membrane and aggregates of purified LPS, making even more remarkable its picomolar potency and the ability of discrete variations in lipid A structure to markedly alter the pro-inflammatory activity of LPS. Two recognition systems—MD-2/TLR4 and “LPS-sensing” cytosolic caspases—together confer LPS responsiveness at the host cell surface, within endosomes, and at sites physically accessible to the cytosol. Understanding how the lipid A of LPS is delivered and recognized at these diverse sites is crucial to understanding how the magnitude and character of the inflammatory responses are regulated.