Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR

Innate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-like receptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatory signals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect the immune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DCs) are exacerbated by a high-fatty-acid (FA) metabolic environment. FAs suppress the TLR-induced hexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changes enhance mitochondrial reactive oxygen species (mtROS) production and, in turn, the unfolded protein response (UPR), leading to a distinct transcriptomic signature with IL-23 as hallmark. Interestingly, chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response. Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23 expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innate immunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR. [Display omitted] •Extracellular FAs inhibit HK activity and rewire metabolism in late TLR activation•FA-mediated adaptation of glycolysis leads to perturbed mitochondrial fitness•Metabolic adaptation and mitochondrial ROS exacerbate TLR-induced UPR activation•The UPR links metabolic alterations to a distinct inflammatory signature A high-fat diet induces the metabolic rewiring of TLR-activated dendritic cells and exacerbates IL-23-mediated psoriatic skin inflammation.