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

Denis Mogilenko 1, 2 Joel Haas 1, 2 Laurent L’homme 1, 2 Sébastien Fleury 1, 2 Sandrine Quemener 1, 2 Matthieu Levavasseur 1, 2 Coralie Becquart 1, 2 Julien Wartelle 1, 2 Alexandra Bogomolova 1, 2 Laurent Pineau 1, 2 Olivier Molendi-Coste 1, 2 Steve Lancel 1, 2 Hélène Dehondt 1, 2 Celine Gheeraert 1, 2 Aurelie Melchior 1, 2 Cédric Dewas 1, 2 Artemii Nikitin 1, 2 Samuel Pic 1, 2 Nabil Rabhi 2, 3, 4 Jean-Sébastien Annicotte 2, 3, 4 Seiichi Oyadomari 5 Talia Velasco-Hernandez 6 Jörg Cammenga 6 Marc Foretz 7 Benoit Viollet 7 Milica Vukovic 8 Arnaud Villacreces 8 Kamil Kranc 8 Peter Carmeliet 9 Guillemette Marot 10 Alexis Boulter 11 Simon Tavernier 12 Luciana Berod 13 Maria Longhi 8 Christophe Paget 14 Sophie Janssens 12 Delphine Staumont-Sallé 1, 2 Ezra Aksoy 8 Bart Staels 1, 2 David Dombrowicz 1, 2
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.
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Submitted on : Tuesday, October 5, 2021 - 10:19:13 AM
Last modification on : Wednesday, November 3, 2021 - 2:59:04 PM

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Denis Mogilenko, Joel Haas, Laurent L’homme, Sébastien Fleury, Sandrine Quemener, et al.. Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR. Cell, Elsevier, 2019, 177 (5), pp.1201-1216.e19. ⟨10.1016/j.cell.2019.03.018⟩. ⟨hal-03365057⟩

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