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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1354074

Formyl peptide receptor 2 (FPR2) regulates dendritic cell metabolism and Th17 cell differentiation during neuroinflammation

Provisionally accepted
Jong-Hyung Lim Jong-Hyung Lim 1*Ales Neuwirth Ales Neuwirth 2Kyoung-Jin Chung Kyoung-Jin Chung 3Sylvia Grossklaus Sylvia Grossklaus 3Oliver Soehnlein Oliver Soehnlein 4George Hajishengallis George Hajishengallis 1Triantafyllos Chavakis Triantafyllos Chavakis 3
  • 1 Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • 2 Laboratory of Adaptive Immunity, Laboratory of Adaptive Immunity, Prague, Prague, Czechia
  • 3 Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Dresden, Lower Saxony, Germany
  • 4 Institute for Experimental Pathology, Center for Molecular Biology of Inflammation, University of Münster, Münster, North Rhine-Westphalia, Germany

The final, formatted version of the article will be published soon.

    Formyl peptide receptor 2 (FPR2) is a receptor for formylated peptides and specific pro-resolving mediators, and is involved in various inflammatory processes. Here, we aimed to elucidate the role of FPR2 in dendritic cell (DC) function and autoimmunity-related central nervous system (CNS) inflammation by using the experimental autoimmune encephalomyelitis (EAE) model. EAE induction was accompanied by increased Fpr2 mRNA expression in the spinal cord. FPR2-deficient (Fpr2KO) mice displayed delayed onset of EAE compared to wild-type (WT) mice, associated with reduced frequencies of Th17 cells in the inflamed spinal cord at the early stage of the disease. However, FPR2 deficiency did not affect EAE severity after the disease reached its peak. FPR2 deficiency in mature DCs resulted in decreased expression of Th17 polarizing cytokines IL6, IL23p19, IL1β, and thereby diminished the DC-mediated activation of Th17 cell differentiation. LPS-activated FPR2-deficient DCs showed upregulated Nos2 expression and nitric oxide (NO) production, as well as reduced oxygen consumption rate and impaired mitochondrial function, including decreased mitochondrial superoxide levels, lower mitochondrial membrane potential and diminished expression of genes related to the tricarboxylic acid cycle and genes related to the electron transport chain, as compared to WT DCs. Treatment with a NO inhibitor reversed the reduced Th17 cell differentiation in the presence of FPR2-deficient DCs. Together, by regulating DC metabolism, FPR2 enhances the production of DC-derived Th17-polarizing cytokines and hence Th17 cell differentiation in the context of neuroinflammation.

    Keywords: Formyl peptide receptor 2, Dendritic Cells, Th17 Cells, Nitric Oxide, Metabolism Experimental autoimmune encephalomyelitis

    Received: 11 Dec 2023; Accepted: 18 Jul 2024.

    Copyright: © 2024 Lim, Neuwirth, Chung, Grossklaus, Soehnlein, Hajishengallis and Chavakis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Jong-Hyung Lim, Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, 19104-6030, Pennsylvania, United States

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