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

• Published in: Cell Vol. 177; no. 5; pp. 1201 - 1216.e19
• Main Authors: Mogilenko, Denis A., Haas, Joel T., L’homme, Laurent, Fleury, Sébastien, Quemener, Sandrine, Levavasseur, Matthieu, Becquart, Coralie, Wartelle, Julien, Bogomolova, Alexandra, Pineau, Laurent, Molendi-Coste, Olivier, Lancel, Steve, Dehondt, Hélène, Gheeraert, Celine, Melchior, Aurelie, Dewas, Cédric, Nikitin, Artemii, Pic, Samuel, Rabhi, Nabil, Annicotte, Jean-Sébastien, Oyadomari, Seiichi, Velasco-Hernandez, Talia, Cammenga, Jörg, Foretz, Marc, Viollet, Benoit, Vukovic, Milica, Villacreces, Arnaud, Kranc, Kamil, Carmeliet, Peter, Marot, Guillemette, Boulter, Alexis, Tavernier, Simon, Berod, Luciana, Longhi, Maria P., Paget, Christophe, Janssens, Sophie, Staumont-Sallé, Delphine, Aksoy, Ezra, Staels, Bart, Dombrowicz, David
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.05.2019
• Subjects: Animals; Cellular Microenvironment - genetics; Cellular Microenvironment - immunology; Citric Acid Cycle - genetics; Citric Acid Cycle - immunology; dendritic cells; Dendritic Cells - immunology; Dendritic Cells - pathology; fatty acids; glycolysis; hexokinase; Hexokinase - genetics; Hexokinase - immunology; IL-23; Immunity, Innate; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; innate immunity; metabolic reprogramming; Mice; Mice, Knockout; Mitochondria - genetics; Mitochondria - immunology; mtROS; psoriasis; Reactive Oxygen Species - immunology; Toll-Like Receptors - genetics; Toll-Like Receptors - immunology; Unfolded Protein Response - genetics; Unfolded Protein Response - immunology; UPR; X-Box Binding Protein 1 - genetics; X-Box Binding Protein 1 - immunology; dendritic cells; innate immunity; fatty acids; UPR; psoriasis; glycolysis; mtROS; IL-23; metabolic reprogramming; hexokinase
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2019.03.018

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.