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

Denis A. Mogilenko, Joel T. Haas, Laurent L'homme, Sébastien Fleury, Sandrine Quemener, Matthieu Levavasseur, Coralie Becquart, Julien Wartelle, Alexandra Bogomolova, Laurent Pineau, Olivier Molendi-Coste, Steve Lancel, Hélène Dehondt, Celine Gheeraert, Aurelie Melchior, Cédric Dewas, Artemii Nikitin, Samuel Pic, Nabil Rabhi, Jean Sébastien AnnicotteSeiichi Oyadomari, Talia Velasco-Hernandez, Jörg Cammenga, Marc Foretz, Benoit Viollet, Milica Vukovic, Arnaud Villacreces, Kamil Kranc, Peter Carmeliet, Guillemette Marot, Alexis Boulter, Simon Tavernier, Luciana Berod, Maria P. Longhi, Christophe Paget, Sophie Janssens, Delphine Staumont-Sallé, Ezra Aksoy, Bart Staels, David Dombrowicz

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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. A high-fat diet induces the metabolic rewiring of TLR-activated dendritic cells and exacerbates IL-23-mediated psoriatic skin inflammation.

Original languageEnglish
Pages (from-to)1201-1216.e19
JournalCell
Volume177
Issue number5
DOIs
StatePublished - May 16 2019

Keywords

  • IL-23
  • UPR
  • dendritic cells
  • fatty acids
  • glycolysis
  • hexokinase
  • innate immunity
  • metabolic reprogramming
  • mtROS
  • psoriasis

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