Effects of Differences in Lipid A Structure on TLR4 Pro-Inflammatory Signaling and Inflammasome Activation.

The vertebrate immune system exists in equilibrium with the microbial world. The innate immune system recognizes pathogen-associated molecular patterns via a family of Toll-like receptors (TLR) that activate cells upon detection of potential pathogens. Because some microbes benefit their hosts, mobilizing the appropriate response, and then controlling that response is critical in the maintenance of health.

Mechanism of impaired NLRP3 inflammasome priming by monophosphoryl lipid A.

Monophosphoryl lipid A (MLA), a nontoxic derivative of the endotoxin lipopolysaccharide (LPS), has been approved in the United States for use as a vaccine adjuvant. LPS and MLA are ligands of Toll-like receptor 4 (TLR4), and it has been unclear why LPS triggers toxic inflammation, whereas MLA generates safe and effective immunostimulation. Signaling downstream of TLR4 is mediated by the adaptor proteins TRIF [Toll-interleukin-1 (IL-1) receptor (TIR) domain-containing adaptor-inducing interferon-β], which is required for adaptive immune outcomes, and MyD88 (myeloid differentiation marker 88), which is responsible for many proinflammatory effects.