Dimerization of these molecules with another lipid A-MD2-TLR4 complex creates a functional TLR4 signaling complex (47). acid metabolism, between TLR9 and IDO, and between STING and autophagy. These initial works highlight the potential for harnessing the induction of antiviral CD8+ T-cell responses using synergistic modulation of metabolic and PRR pathways. fatty acid synthesis (FAS) (23), required for the production of membranes to expand organelles (23). Interestingly, FAS is usually induced also after T-cell activation, and necessary for their growth (12, 40). The induction of FAS upon PRR and TCR activation leads to the storage of fatty acids in lipid droplets (23, 41), whose function still remains controversial. Indeed, DCs with high content of lipids have been shown to better activate T-cells in the PKP4 liver (42) but displayed diminished priming capacity within tumors (43). In addition, while storage of FA into triacylglycerol may be a mechanism exerted to avoid lipotoxicity (44), extra on neutral lipids has also been shown to induce apoptosis in T-cells (45). Interplay between TLR4 and fatty acid metabolism The canonical Toll-like receptor 4 (TLR4) signaling cascade is initiated when lipid A (the membrane anchor of lipopolysaccharide [LPS]) is usually bound by the extracellular region of CD14, which complexes with MD2 and binds to membrane-bound TLR4 (46). Dimerization of these molecules with another lipid A-MD2-TLR4 complex creates a functional TLR4 signaling complex (47). Binding of a TLR4 agonist like lipid A initiates an innate immune response that can drive the development of antigen-specific acquired immunity (48). Mimicking the innate sensing of molecular patterns derived from microbespathogenic and non-pathogenicto activate of immune cells, TLR4 agonist molecules show great promise for use as immunotherapeutic adjuvants to potentiate host responses in component vaccines [Examined in Reed et al. (48)]. With respect to metabolism, TLR4 activation has been linked with FA-induced inflammation in a number of pathologic conditions, including insulin resistance, retinal impairment, atherosclerosis and myocardial Diosbulbin B injury observed during diabetes and obesity (49C54). Long chain, saturated FAs (SFAs) require TLR4 to exert pro-inflammatory effects (55), and have been suggested to bind it (53, 56). Lipid A itself is usually acylated with SFAs (57), whose number, length and saturation determine the TLR4 agonistic properties of LPS (49, 57). Conversely, poly-unsaturated FAs (PUFAs) inhibit TLR4 activation (49, 58). Notably, a similar pattern has been shown for another bacterial cell Diosbulbin B wall sensor, TLR2 (59). More recently, it has been proposed that SFAs Diosbulbin B may act as agonists of TLR4 without binding it (55, 60). SFAs may indeed be able to induce TLR4 dimerization in lipid rafts, in a ligand-independent manner (61), a step that is inhibited by PUFA. Irrespective of the mechanisms, evidence is usually concordant in suggesting that saturated and polyunsaturated FAs exert reverse effects on TLR4-mediated inflammatory response and APC activation. Indeed, SFAs may up-regulate the expression of costimulatory molecules and cytokines, resulting in increased T-cell activation capacity, while these effects are inhibited by PUFA (62). Several lines of evidence suggest that PUFA may reduce the induction of T-cell responses (63C65), acting on both APCs and T-cells. In addition to preventing TLR4 dimerization in lipid rafts and inhibiting downstream kinases (61, 66), PUFA can affect lipid rafts composition in T-cells, altering TCR signaling (67, 68) and resulting in hampered T-cell functionality (68C70). Overall, SFAs may favor co-stimulation delivered by APCs to T-cells and favor both TLR4 and TCR signaling (71), thus Diosbulbin B potentially improving priming capacity (Physique ?(Figure1A1A). Open in a separate window Physique 1 Schematic representation of the interplay between (A) TLR4 and fatty acid metabolism, (B) TLR9 and IDO, and (C) STING and autophagy. (A) TLR4 activation on APCs improves CD8+ T-cell priming. In addition to LPS, SFA are also thought to trigger TLR4. However, it has also been proposed that SFA take action on TLR4-downstream pathways. In contrast, PUFA display anti-inflammatory effects, by dampening both TLR4- and TCR-induced signaling. (B) Dual role of TLR9 activation on T-cell activation. The TLR9 ligand CpG shows adjuvant effects, improving the co-stimulation delivered by APCs to T-cells. However, some reports highlighted that this same pathway may also trigger unfavorable regulators of immunity, such as IDO that down-modulates Diosbulbin B APC-provided co-stimulation and favors Treg activity. Furthermore, IDO mediates tryptophan deprivation, with has negative effects on.