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

Hu, Zhaolan and Zhao, Tuantuan V. and Huang, Tao and Ohtsuki, Shozo and Jin, Ke and Goronzy, Isabel N. and Wu, Bowen and Abdel, Matthew P. and Bettencourt, Jacob W. and Berry, Gerald J. and Goronzy, Jörg J. and Weyand, Cornelia M. (2022) The transcription factor RFX5 coordinates antigen-presenting function and resistance to nutrient stress in synovial macrophages. Nature Metabolism, 4 (6). pp. 759-774. ISSN 2522-5812. doi:10.1038/s42255-022-00585-x. https://resolver.caltech.edu/CaltechAUTHORS:20220707-978162000

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s42255-022-00585-xDOIArticle
https://rdcu.be/cRcGSPublisherFree ReadCube access
ORCID:
AuthorORCID
Hu, Zhaolan0000-0003-1137-0579
Zhao, Tuantuan V.0000-0002-8365-2738
Ohtsuki, Shozo0000-0001-8954-5709
Goronzy, Isabel N.0000-0002-6713-9192
Goronzy, Jörg J.0000-0001-7670-1856
Weyand, Cornelia M.0000-0003-2230-9802
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.
Funders:
Funding AgencyGrant Number
NIHR01AR042527
NIHR01AI108906
NIHR01HL142068
NIHP01HL129941
NIHR01AI108891
NIHR01AG045779
NIHU19AI057266
NIHR01AI129191
Encrantz Family Discovery FundUNSPECIFIED
Issue or Number:6
DOI:10.1038/s42255-022-00585-x
Record Number:CaltechAUTHORS:20220707-978162000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220707-978162000
Official Citation:Hu, Z., Zhao, T.V., Huang, T. et al. The transcription factor RFX5 coordinates antigen-presenting function and resistance to nutrient stress in synovial macrophages. Nat Metab 4, 759–774 (2022). https://doi.org/10.1038/s42255-022-00585-x
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:115420
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:08 Jul 2022 23:12
Last Modified:25 Jul 2022 23:13

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