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

Denis A 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) , Céline Gheeraert (1) , Aurélie Melchior (1) , Cédric Dewas (1) , Artemii Nikitin (1) , Samuel Pic (1) , Nabil Rabhi (3) , Jean-Sébastien Annicotte (3, 4) , Seiichi Oyadomari (5) , Talia Velasco-Hernandez (6) , Jörg Cammenga (6) , Marc Foretz (7, 8) , Benoit Viollet (7, 8) , Milica Vukovic (9) , Arnaud Villacreces (9) , Kamil Kranc (9) , Peter Carmeliet (10, 11) , Guillemette Marot (12) , Alexis Boulter (13) , Simon J. Tavernier (14) , Luciana Berod (15) , Maria P. Longhi (16) , Christophe Paget (17) , Sophie Janssens (18) , Delphine Staumont-Sallé (1, 19) , Ezra Aksoy (20) , Bart Staels (1) , David Dombrowicz (1)

1 RNMCD - Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011
2 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
3 EGENODIA (GI3M) - Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283
4 RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167
5 Institute of Advanced Medical Sciences - Fujii Memorial Institute of Medical Sciences [Tokushima, Japan]
6 Institute for Clinical and Experimental Medicine - Department of Hematology [Linköping, Sweden]
7 IC UM3 (UMR 8104 / U1016) - Institut Cochin
8 USPC - Université Sorbonne Paris Cité
9 Barts Cancer Institute - Centre for Haemato-Oncology [London, UK]
10 Laboratory of Angiogenesis and Vascular Metabolism [Leuven, Belgium]
11 VIB-CCB - Laboratory of Angiogenesis and Vascular Metabolism [Leuven, Belgium]
12 MODAL - MOdel for Data Analysis and Learning
13 UF - University of Florida [Gainesville]
14 Unit of Immunoregulation and Mucosal Immunology [Ghent, Belgium]
15 MHH - Medizinische Hochschule Hannover = Hannover Medical School
16 NIHR Barts Biomedical Research Centre - The William Harvey Research Institute [London, UK]
17 PRPA - Pathologies Respiratoires : Protéolyse et Aérosolthérapie
18 ER Stress and Inflammation [Ghent, Belgium]
19 Département de Dermatologie [CHRU Lille]
20 William Harvey Research Institute - Centre for Biochemical Pharmacology [London, UK]

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.

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

Domaines: Pneumologie et système respiratoire; Immunologie; Dermatologie

Denis A 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, In press, 177 (5), pp.1201-1216.e19. ⟨10.1016/j.cell.2019.03.018⟩. ⟨inserm-02084447⟩