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Cell. 2019 May 16;177(5):1201-1216.e19. doi: 10.1016/j.cell.2019.03.018. Epub 2019 Apr 25.

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

Author information

1
University of Lille, EGID, INSERM, CHU Lille, Institut Pasteur de Lille, U1011, 59019 Lille, France.
2
University of Lille, EGID, INSERM, CHU Lille, Institut Pasteur de Lille, U1011, 59019 Lille, France; Department of Dermatology, CHU Lille, 59045 Lille, France.
3
University of Lille, EGID, CNRS, CHU Lille, Institut Pasteur de Lille, UMR 8199, 59019 Lille, France.
4
Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.
5
Department of Hematology, Institute for Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.
6
Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS, UMR8104, 75014 Paris, France.
7
Centre for Haemato-Oncology, Barts, and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
8
Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, University of Leuven, Leuven, 3000 Belgium.
9
Université Lille, MODAL Team, Inria Lille-Nord Europe, 59650 Villeneuve-d'Ascq, France.
10
University of Florida College of Medicine, Gainesville, FL 32610, USA.
11
Laboratory of Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research and Department of Internal Medicine and Pediatrics, Ghent University, 9052 Ghent, Belgium.
12
Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Niedersachsen 30625, Germany.
13
William Harvey Research Institute, Barts, and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
14
Université de Tours, INSERM, Centre d'Etude des Pathologies Respiratoires (CEPR), UMR 1100, 37041 Tours, France.
15
ER Stress and Inflammation, VIB Center for Inflammation Research, and Department of Internal Medicine and Pediatrics, Ghent University, 9052 Ghent, Belgium.
16
Centre for Biochemical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK.
17
University of Lille, EGID, INSERM, CHU Lille, Institut Pasteur de Lille, U1011, 59019 Lille, France. Electronic address: david.dombrowicz@pasteur-lille.fr.

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

PMID:
31031005
DOI:
10.1016/j.cell.2019.03.018

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