Inhibition of fatty acid metabolism by etomoxir or TOFA suppresses murine dendritic cell activation without affecting viability

Abstract

Objective: Dendritic cells (DCs) are important players in immunity against pathogens, but overactive DCs have been implicated in autoimmune diseases, like lupus, in which a paucity of targeted therapies remains. Recent research shows that DCs upregulate their immunometabolism when activating. We explored whether modulating fatty acid (FA) metabolism needed for oxidative phosphorylation can affect the activation of two main DC subsets.

Material and methods: Sorted murine plasmacytoid DCs (pDCs) and conventional DCs (cDCs), generated in FLT3-L medium, were treated with etomoxir, an inhibitor of FA oxidation, or TOFA, an inhibitor of FA synthesis, then stimulated with TLR9 agonist CpGA. Surface activation markers and viability were analyzed by flow cytometry, cytokine, and chemokine production and were measured by ELISA.

Results: Modulation of FA metabolism suppressed the upregulation of costimulatory molecules and the production of proinflammatory cytokine IL-6 and type I Interferon-dependent chemokine CXCL10 by both subsets of DCs, without affecting DC viability, neither of resting DCs or upon activation. Etomoxir inhibited pDCs at lower doses than cDCs, suggesting that pDCs may be more susceptible to FA metabolic modulation.

Conclusions: Both cDCs, the primary antigen presenting cell, and pDCs, the primary type I IFN producer, exhibit a suppressed ability to activate but normal viability when their FA metabolism is inhibited by etomoxir or TOFA. Our findings indicate that FA metabolism plays an important role in the activation of both pDCs and cDCs and suggest that its modulation is an exploitable therapeutic target to suppress DC activation in inflammation or autoimmunity.

Keywords:

• Dendritic cell activation
• plasmacytoid dendritic cell
• conventional dendritic cell
• etomoxir
• TOFA
• 5-(Tetradecyloxy)-2-furoic Acid
• fatty acid oxidation
• fatty acid synthase
• systemic lupus erythematosus
• pro-inflammatory cytokines
• immunometabolism

Acknowledgments

We would like to thank the Temple Infections and Autoimmunity Interest Group for stimulating discussions.

Disclosure statement

No financial benefit has arisen from the findings in this research. No conflicts of interest are reported by any of the authors.

Additional information

Funding

This work was supported by the U.S., National Institutes of Health, NIAD, R21 AI119947 (SG), and the Lupus Foundation of America, under the Goldie Simon Preceptorship Award (CCQ).