Research ArticleImmunology

Mechanism of Impaired NLRP3 Inflammasome Priming by Monophosphoryl Lipid A

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Science Signaling  03 May 2011:
Vol. 4, Issue 171, pp. ra28
DOI: 10.1126/scisignal.2001486

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Beneficial Bias

A successful vaccine adjuvant must stimulate the immune system without triggering harmful inflammatory side effects. Stimulation of Toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) induces a toxic inflammatory response, characterized by induction and assembly of the NLRP3 inflammasome and production of the proinflammatory cytokine interleukin-1β (IL-1β). TLR4 signaling in response to the LPS derivative monophosphoryl lipid A (MLA) is orders of magnitude less toxic than that stimulated by LPS; however, how these compounds elicit such different responses through the same receptor is unclear. Embry et al. provide evidence that MLA induced one arm of TLR4 signaling (through the adaptor protein TRIF), such that small quantities of the precursor form of IL-1β were synthesized, but that induction and assembly of the inflammasome and production of active IL-1β were defective. These processes instead depended on the second arm of TLR4 signaling, mediated by the adaptor MyD88, which was only activated by LPS. In addition, priming of cells with MLA dampened subsequent TLR4-dependent responses because of failed assembly of the inflammasome. Together, these data highlight a potential mechanism for the beneficial effects of MLA.