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

Denis Mogilenko; Joel 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 Annicotte; Seiichi 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 Longhi; Christophe Paget; Sophie Janssens; Delphine Staumont-Sallé; Ezra Aksoy; Bart Staels; David Dombrowicz

doi:10.1016/j.cell.2019.03.018

Journal articles

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}

1 RNMCD - U1011 - Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires

2 EGID - European Genomic Institute for Diabetes - FR 3508

3 CHU Lille

4 GI3M - Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283

5 Tokushima University

6 LIU - Linköping University

7 IC UM3 (UMR 8104 / U1016) - Institut Cochin

8 QMUL - Queen Mary University of London

9 KU Leuven - Catholic University of Leuven - Katholieke Universiteit Leuven

10 MODAL - MOdel for Data Analysis and Learning

Inria Lille - Nord Europe, LPP - Laboratoire Paul Painlevé - UMR 8524, METRICS - Evaluation des technologies de santé et des pratiques médicales - ULR 2694, Polytech Lille - École polytechnique universitaire de Lille, Université de Lille, Sciences et Technologies

11 The University of Florida College of Medicine

12 UGENT - Ghent University [Belgium]

13 HZI - Helmholtz Centre for Infection Research

14 CEPR - Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100

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.

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

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Journal articles

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Life Sciences [q-bio]

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https://hal-univ-tours.archives-ouvertes.fr/hal-03365057
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Submitted on : Tuesday, October 5, 2021 - 10:19:13 AM
Last modification on : Tuesday, October 19, 2021 - 11:40:31 AM

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

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

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