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

Author:
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
Source:
Cell 2019 v.177 no.5 pp. 1201-1216.e19
ISSN:
0092-8674
Subject:
Toll-like receptors, dendritic cells, enzyme activity, genetic suppression, glycolysis, hexokinase, immune response, inflammation, innate immunity, interleukin-23, mitochondria, models, psoriasis, reactive oxygen species, transcriptomics, tricarboxylic acid cycle, unfolded protein response
Abstract:
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.
Agid:
6441435