Fig. 1.

Retinoic acid signaling orchestrates innate and adaptive immune responses to viral infections. Extracellular and intra-vesicular viruses are recognized through TLR receptors activating the TRAF/IRF signaling cascade. After the viral genome is taken into the cell, the immune response switches to the RIG-I and MDA5 further activating TRAF/IRF pathway. Activated TRAF/IRF leads to Type I IFN synthesis (green arrows, center). RIG-I is synthesized through RAR/RXR (blue arrows, left side) as long as there is sufficient retinoid signaling in the cell, and type I interferon synthesis continues through RIG-I and TLR system (green arrows, center). TRAF can also activate IKK leading to degradation of I-κB and activation of NF-κB. In addition, the MAPK, PI3K/Akt and Jak/STAT pathways are also under the control of non-genomic signaling of retinoic acids. Here, non-genomic signaling cascades are modulated by STRA6 and membrane-associated RARs via RA recruitment, leading to activation or inactivation of NF-B (red arrows, right side). Here, the association of RA with CRABP-1 inhibits tonic MAPK, PI3K/Akt and Jak/STAT signaling. RA activates RIG-I expression (black dotted arrows) and inhibits cytokine feed-forward loop and UPS system (blunt-ended dotted black lines) preventing NF-кB activation through UPS. With retinol depletion, the RIG-I arm of the innate immune system that produces Type I interferon collapses (green arrows, center), but the UPS-NF-κB pathway continues operating through TLR receptors releasing cytokines and other inflammatory mediators (red arrows, right side). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)