Toll-like receptor 4 (TLR4) modulation by synthetic and natural compounds: an update

Toll-like receptor 4 (TLR4), together with MD-2, binds bacterial endotoxins (E) with high affinity, triggering formation of the activated homodimer (E.MD-2.TLR4)2. Activated TLR4 induces intracellular signaling leading to activation of transcription factors that result in cytokine and chemokine production and initiation of inflammatory and immune responses. TLR4 also responds to endogenous ligands called danger associated molecular patterns (DAMPs). Increased sensitivity to infection and a variety of immune pathologies have been associated with either too little or too much TLR4 activation. We review here the molecular mechanisms of TLR4 activation (agonism) or inhibition (antagonism) by small organic molecules of both natural and synthetic origin. The role of co-receptors MD-2 and CD14 in the TLR4 modulation process is also discussed. Recent achievements in the field of chemical TLR4 modulation are reviewed, with special focus on nonclassical TLR4 ligands with a chemical structure different from that of lipid A.