Research ArticleImmunology

Selective TRIF-Dependent Signaling by a Synthetic Toll-Like Receptor 4 Agonist

Sci. Signal.  14 Feb 2012:
Vol. 5, Issue 211, pp. ra13
DOI: 10.1126/scisignal.2001963

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Biasing TLR4 Signaling Toward a Less Inflammatory Route

Signaling downstream of Toll-like receptor 4 (TLR4) proceeds through two pathways that are dependent on distinct adaptor proteins. One of these pathways leads to immunostimulatory responses, whereas the other leads to the production of toxic proinflammatory cytokines. Compounds that could stimulate the beneficial arm rather than the proinflammatory arm would be useful as adjuvants for vaccines. Bowen et al. investigated two synthetic TLR4 agonists that differed only in their stereochemistry at a single point in their structure and found that whereas one agonist stimulated both arms of the TLR4 pathway, the other agonist stimulated only the noninflammatory branch. These findings have implications for the design of more effective vaccine adjuvants.