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Published June 2022 | Accepted Version + Supplemental Material
Journal Article Open

The transcription factor RFX5 coordinates antigen-presenting function and resistance to nutrient stress in synovial macrophages

Abstract

Tissue macrophages (Mϕ) are essential effector cells in rheumatoid arthritis (RA), contributing to autoimmune tissue inflammation through diverse effector functions. Their arthritogenic potential depends on their proficiency to survive in the glucose-depleted environment of the inflamed joint. Here, we identify a mechanism that links metabolic adaptation to nutrient stress with the efficacy of tissue Mϕ to activate adaptive immunity by presenting antigen to tissue-invading T cells. Specifically, Mϕ populating the rheumatoid joint produce and respond to the small cytokine CCL18, which protects against cell death induced by glucose withdrawal. Mechanistically, CCL18 induces the transcription factor RFX5 that selectively upregulates glutamate dehydrogenase 1 (GLUD1), thus enabling glutamate utilization to support energy production. In parallel, RFX5 enhances surface expression of HLA-DR molecules, promoting Mϕ-dependent expansion of antigen-specific T cells. These data place CCL18 at the top of a RFX5–GLUD1 survival pathway and couple adaptability to nutrient conditions in the tissue environment to antigen-presenting function in autoimmune tissue inflammation.

Additional Information

© 2022 Springer Nature Limited. Received 04 March 2022. Accepted 16 May 2022. Published 23 June 2022. Issue Date June 2022. This work was supported by the National Institutes of Health (R01AR042527, R01AI108906, R01HL142068, and P01HL129941 to CMW and R01AI108891, R01AG045779, U19AI057266, R01AI129191 to J.J.G.) and by the Encrantz Family Discovery Fund. These authors contributed equally: Zhaolan Hu, Tuantuan V. Zhao. Contributions. Conceptualization, C.M.W., J.J.G.; Formal Analysis, Z.H., T.V.Z.; Investigation, Z.H., T.V.Z., T.H., S.O., K.J., I.N.G., B.W., G.J.B.; Clinical Samples, M.P.A., J.W.B.; Writing (original), C.M.W., Z.H., T.V.Z., I.N.G.; Supervision, C.M.W., J.J.G., G.J.B.; Funding Acquisition, C.M.W., J.J.G. Data availability. All data that support the findings of this study are available from the corresponding author upon reasonable request. Source data are provided with this paper. The authors have no competing interests. Peer review information. Nature Metabolism thanks Anne Davidson, Ping-Chih Ho and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Editor recognition statement Primary handling editors: Alfredo Gimenez-Cassina and George Caputa, in collaboration with the Nature Metabolism team.

Attached Files

Accepted Version - nihms-1818981.pdf

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Additional details

Created:
August 22, 2023
Modified:
October 24, 2023