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.
Highlights
Endotoxins are abundant surface lipopolysaccharides (LPS) of Gram-negative bacteria (GNB) that can potently induce both protective and potentially harmful inflammatory responses in humans and other mammals[1]
The structurally unique lipid A region of LPS that is normally embedded within the GNB outer membrane (OM) is the principal determinant of both MD-2/TLR4 and caspase activation[1,4,5,6]
The fundamental challenge faced by cytosolic caspases is in part the same as for the MD-2/TLR4 system: how does the host recognize specific structural features of a lipid that is normally buried in the GNB OM? Because of the cytosolic location of the LPS-sensing caspases, additional questions include (1) how is caspase-activating LPS delivered to cytosolic caspases and (2) how are LPS structure recognition and caspase activation achieved? the non-canonical inflammasome seems to share with MD-2/TLR4 a preference for hexa-acyl phosphorylated lipid A/LPS4–6,75, the data that we review below suggest that the mechanisms for LPS-induced non-canonical inflammasome activation are different from those of the MD-2/TLR4 system
Summary
F1000 Faculty Reviews are commissioned from members of the prestigious F1000 Faculty. In order to make these reviews as comprehensive and accessible as possible, peer review takes place before publication; the referees are listed below, but their reports are not formally published
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