Metabolic and innate immune cues merge into a specific inflammatory response via unfolded protein response (UPR)

Denis Mogilenko 1 Joël Haas 1 Laurent l'Homme 1 Sébastien Fleury 1 Sandrine Quemener 1 Matthieu Levavasseur 1, 2 Coralie Becquart 1, 2 Julien Wartelle 1 Alexandra Bogomolova 1 Laurent Pineau 1 Olivier Molendi-Coste 1 Steve Lancel 1 Hélène Dehondt 1 Celine Gheeraert 1 Aurélie Melchior 1 Cédric Dewas 1 Artemii Nikitin 1 Samuel Pic 1 Nabil Rabhi 3 Jean-Sébastien Annicotte 3 Seiichi Oyadomari 4 Talia Velasco-Hernandez 5 Jörg Cammenga 5 Marc Foretz 6, 7 Benoit Viollet 6, 7 Milica Vukovic 8 Arnaud Villacreces 8 Kamil Kranc 8 Peter Carmeliet 9, 10 Guillemette Marot 11 Alexis Boulter 12 Simon Tavernier 13 Luciana Berod 14 Maria Longhi 15 Christophe Paget 16 Sophie Janssens 17 Delphine Staumont-Sallé 1, 18 Ezra Aksoy 19 Bart Staels 1 David Dombrowicz 1, *
* Corresponding author
11 MODAL - MOdel for Data Analysis and Learning
Inria Lille - Nord Europe, LPP - Laboratoire Paul Painlevé - UMR 8524, CERIM - Santé publique : épidémiologie et qualité des soins-EA 2694, Polytech Lille - École polytechnique universitaire de Lille, Université de Lille, Sciences et Technologies
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 (DC) are exacerbated by a high fatty acid (FA) metabolic environment. FA 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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Denis Mogilenko, Joël Haas, Laurent l'Homme, Sébastien Fleury, Sandrine Quemener, et al.. Metabolic and innate immune cues merge into a specific inflammatory response via unfolded protein response (UPR). Cell, Elsevier, In press, 177 (5), pp.1201-1216.e19. ⟨10.1016/j.cell.2019.03.018⟩. ⟨inserm-02084447⟩

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