TY - JOUR
T1 - Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR
AU - Mogilenko, Denis A.
AU - Haas, Joel T.
AU - L'homme, Laurent
AU - Fleury, Sébastien
AU - Quemener, Sandrine
AU - Levavasseur, Matthieu
AU - Becquart, Coralie
AU - Wartelle, Julien
AU - Bogomolova, Alexandra
AU - Pineau, Laurent
AU - Molendi-Coste, Olivier
AU - Lancel, Steve
AU - Dehondt, Hélène
AU - Gheeraert, Celine
AU - Melchior, Aurelie
AU - Dewas, Cédric
AU - Nikitin, Artemii
AU - Pic, Samuel
AU - Rabhi, Nabil
AU - Annicotte, Jean Sébastien
AU - Oyadomari, Seiichi
AU - Velasco-Hernandez, Talia
AU - Cammenga, Jörg
AU - Foretz, Marc
AU - Viollet, Benoit
AU - Vukovic, Milica
AU - Villacreces, Arnaud
AU - Kranc, Kamil
AU - Carmeliet, Peter
AU - Marot, Guillemette
AU - Boulter, Alexis
AU - Tavernier, Simon
AU - Berod, Luciana
AU - Longhi, Maria P.
AU - Paget, Christophe
AU - Janssens, Sophie
AU - Staumont-Sallé, Delphine
AU - Aksoy, Ezra
AU - Staels, Bart
AU - Dombrowicz, David
N1 - Funding Information:
This work was supported in part by grants from ANR and the European Union (EGID ANR-10-LABX-46 to B.S. and D.D. and ANR-17-CE15-0030-02 to B.V.), a National Psoriasis Foundation (USA) Early Career Research Grant (to D.A.M.), an EMBO Long-Term Fellowship (to J.T.H.), an MRC grant (MR/M023230/1 to E.A.), and CRUK grants (C29967/A14633 and C29967/A26787 to K.K.). B.S. is recipient of an ERC advanced grant (ERC-2016-AdG-694717). We thank members of the Bart Staels lab for help with experiments, Jean-Claude Sirard (Institut Pasteur de Lille, France), Juan R. Cubillos-Ruiz and Laurie H. Glimcher (Weill Cornell Medical College, New York, USA), Eik Hoffmann (Institut Pasteur de Lille, France) for mice, and Morten Danielsen and Lea Johnsen (MS-Omics, Copenhagen, Denmark) for assistance with LC-MS and GC-MS. D.A.M. J.T.H. D.S.S. E.A. and D.D. designed the study, analyzed the data, and wrote the manuscript with input from the other authors. B.S. discussed the data and edited the manuscript. D.A.M. J.T.H. L.L. S.F. S.Q. M.L. C.B. S.L. A.B. D.S.-S. E.A. and D.D. performed the experiments with assistance from J.W. L.P. O.M.-C. H.D. C.G. A.M. C.D. A.N. A.B. S.P. and N.R. Important mice, reagents, and experimental and data analysis techniques were provided by J.-S.A. S.O. T.V.-H. J.C. M.F. B.V. M.V. A.V. K.K. G.M. S.T. C.P. P.C. L.B. M.P.L. and S.J. The authors declare no competing interests.
Funding Information:
This work was supported in part by grants from ANR and the European Union ( EGID ANR-10-LABX-46 to B.S. and D.D. and ANR-17-CE15-0030-02 to B.V.), a National Psoriasis Foundation (USA) Early Career Research Grant (to D.A.M.), an EMBO Long-Term Fellowship (to J.T.H.), an MRC grant ( MR/M023230/1 to E.A.), and CRUK grants ( C29967/A14633 and C29967/A26787 to K.K.). B.S. is recipient of an ERC advanced grant ( ERC-2016-AdG-694717 ). We thank members of the Bart Staels lab for help with experiments, Jean-Claude Sirard (Institut Pasteur de Lille, France), Juan R. Cubillos-Ruiz and Laurie H. Glimcher (Weill Cornell Medical College, New York, USA), Eik Hoffmann (Institut Pasteur de Lille, France) for mice, and Morten Danielsen and Lea Johnsen (MS-Omics, Copenhagen, Denmark) for assistance with LC-MS and GC-MS.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/5/16
Y1 - 2019/5/16
N2 - 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.
AB - 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.
KW - IL-23
KW - UPR
KW - dendritic cells
KW - fatty acids
KW - glycolysis
KW - hexokinase
KW - innate immunity
KW - metabolic reprogramming
KW - mtROS
KW - psoriasis
UR - http://www.scopus.com/inward/record.url?scp=85065259821&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2019.03.018
DO - 10.1016/j.cell.2019.03.018
M3 - Article
C2 - 31031005
AN - SCOPUS:85065259821
SN - 0092-8674
VL - 177
SP - 1201-1216.e19
JO - Cell
JF - Cell
IS - 5
ER -