Metabolic Signature and Proteasome Activity Controls Synovial Migration of CD14 Cells in Rheumatoid Arthritis

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2023 Sep 4

PMID 37662900

Authors

Eric Malmhall-Bah

Karin M E Andersson

Malin C Erlandsson

Sofia T Silfversward

Rille Pullerits

Maria I Bokarewa

Affiliations

Soon will be listed here.

Abstract

Objective: Activation of Rho-GTPases in macrophages causes inflammation and severe arthritis in mice. In this study, we explore if Rho-GTPases define the joint destination of pathogenic leukocytes, the mechanism by which they perpetuate rheumatoid arthritis (RA), and how JAK inhibition mitigates these effects.

Methods: CD14 cells of 136 RA patients were characterized by RNA sequencing and cytokine measurement to identify biological processes and transcriptional regulators specific for CD14 cells, which were summarized in a metabolic signature (MetSig). The effect of hypoxia and IFN-γ signaling on the metabolic signature of CD14 cells was assessed experimentally. To investigate its connection with joint inflammation, the signature was translated into the single-cell characteristics of synovial tissue macrophages. The sensitivity of MetSig to the RA disease activity and the treatment effect were assessed experimentally and clinically.

Results: CD14 cells carried MetSig of genes functional in the oxidative phosphorylation and proteasome-dependent cell remodeling, which correlated with the cytokine-rich migratory phenotype and antigen-presenting capacity of these cells. Integration of CD14 and synovial macrophages marked with MetSig revealed the important role of the interferon-rich environment and immunoproteasome expression in the homeostasis of these pathogenic macrophages. The CD14 cells were targeted by JAK inhibitors and responded with the downregulation of immunoproteasome and MHC-II molecules, which disintegrated the immunological synapse, reduced cytokine production, and alleviated arthritis.

Conclusion: This study shows that the CDC42-related MetSig identifies the antigen-presenting CD14 cells that migrate to joints to coordinate autoimmunity. The accumulation of CD14 cells discloses patients perceptive to the JAKi treatment.

References

Andersson K, Turkkila M, Erlandsson M, Bossios A, Toyra Silfversward S, Hu D . Survivin controls biogenesis of microRNA in smokers: A link to pathogenesis of rheumatoid arthritis. Biochim Biophys Acta Mol Basis Dis. 2016; 1863(3):663-673. DOI: 10.1016/j.bbadis.2016.11.033. View

Waku T, Nakamura N, Koji M, Watanabe H, Katoh H, Tatsumi C . NRF3-POMP-20S Proteasome Assembly Axis Promotes Cancer Development via Ubiquitin-Independent Proteolysis of p53 and Retinoblastoma Protein. Mol Cell Biol. 2020; 40(10). PMC: 7189095. DOI: 10.1128/MCB.00597-19. View

Hao Y, Hao S, Andersen-Nissen E, Mauck 3rd W, Zheng S, Butler A . Integrated analysis of multimodal single-cell data. Cell. 2021; 184(13):3573-3587.e29. PMC: 8238499. DOI: 10.1016/j.cell.2021.04.048. View

Khan O, Akula M, Skalen K, Karlsson C, Stahlman M, Young S . Targeting GGTase-I activates RHOA, increases macrophage reverse cholesterol transport, and reduces atherosclerosis in mice. Circulation. 2013; 127(7):782-90. PMC: 3940160. DOI: 10.1161/CIRCULATIONAHA.112.000588. View

Kotschi S, Jung A, Willemsen N, Ofoghi A, Proneth B, Conrad M . NFE2L1-mediated proteasome function protects from ferroptosis. Mol Metab. 2022; 57:101436. PMC: 8814388. DOI: 10.1016/j.molmet.2022.101436. View

Clayton S, MacDonald L, Kurowska-Stolarska M, Clark A . Mitochondria as Key Players in the Pathogenesis and Treatment of Rheumatoid Arthritis. Front Immunol. 2021; 12:673916. PMC: 8118696. DOI: 10.3389/fimmu.2021.673916. View

Goodridge H, Underhill D, Touret N . Mechanisms of Fc receptor and dectin-1 activation for phagocytosis. Traffic. 2012; 13(8):1062-71. DOI: 10.1111/j.1600-0854.2012.01382.x. View

Khan O, Ibrahim M, Jonsson I, Karlsson C, Liu M, Sjogren A . Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice. J Clin Invest. 2011; 121(2):628-39. PMC: 3026725. DOI: 10.1172/JCI43758. View

Welte S, Kuttruff S, Waldhauer I, Steinle A . Mutual activation of natural killer cells and monocytes mediated by NKp80-AICL interaction. Nat Immunol. 2006; 7(12):1334-42. DOI: 10.1038/ni1402. View

10.

Udalova I, Mantovani A, Feldmann M . Macrophage heterogeneity in the context of rheumatoid arthritis. Nat Rev Rheumatol. 2016; 12(8):472-85. DOI: 10.1038/nrrheum.2016.91. View

11.

Miyamoto T, Honda Y, Izawa K, Kanazawa N, Kadowaki S, Ohnishi H . Assessment of type I interferon signatures in undifferentiated inflammatory diseases: A Japanese multicenter experience. Front Immunol. 2022; 13:905960. PMC: 9541620. DOI: 10.3389/fimmu.2022.905960. View

12.

Sha Z, Goldberg A . Proteasome-mediated processing of Nrf1 is essential for coordinate induction of all proteasome subunits and p97. Curr Biol. 2014; 24(14):1573-1583. PMC: 4108618. DOI: 10.1016/j.cub.2014.06.004. View

13.

Alivernini S, MacDonald L, Elmesmari A, Finlay S, Tolusso B, Gigante M . Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nat Med. 2020; 26(8):1295-1306. DOI: 10.1038/s41591-020-0939-8. View

14.

Ng S, Brown L, Stevenson K, DeSouza T, Aster J, Louissaint Jr A . RhoA G17V is sufficient to induce autoimmunity and promotes T-cell lymphomagenesis in mice. Blood. 2018; 132(9):935-947. PMC: 10251505. DOI: 10.1182/blood-2017-11-818617. View

15.

Kim H, Han J, Chan J . Nuclear Factor Erythroid-2 Like 1 (NFE2L1): Structure, function and regulation. Gene. 2016; 584(1):17-25. PMC: 6636332. DOI: 10.1016/j.gene.2016.03.002. View

16.

Pinet V, Vergelli M, Martin R, Bakke O, Long E . Antigen presentation mediated by recycling of surface HLA-DR molecules. Nature. 1995; 375(6532):603-6. DOI: 10.1038/375603a0. View

17.

Ng C, Biniecka M, Kennedy A, McCormick J, FitzGerald O, Bresnihan B . Synovial tissue hypoxia and inflammation in vivo. Ann Rheum Dis. 2010; 69(7):1389-95. PMC: 2946116. DOI: 10.1136/ard.2009.119776. View

18.

Herenius M, Thurlings R, Wijbrandts C, Bennink R, Dohmen S, Voermans C . Monocyte migration to the synovium in rheumatoid arthritis patients treated with adalimumab. Ann Rheum Dis. 2011; 70(6):1160-2. PMC: 3086080. DOI: 10.1136/ard.2010.141549. View

19.

Peng Q, Wan D, Zhou R, Luo H, Wang J, Ren L . The biological function of metazoan-specific subunit nuclear factor related to kappaB binding protein of INO80 complex. Int J Biol Macromol. 2022; 203:176-183. DOI: 10.1016/j.ijbiomac.2022.01.155. View

20.

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View