Metabolic signature and proteasome activity controls synovial migration of CDC42hi CD14+ cells in rheumatoid arthritis

Front Immunol. 2023 Aug 17:14:1187093. doi: 10.3389/fimmu.2023.1187093. eCollection 2023.

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 CDC42 hiCD14+ 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 CDC42 hi synovial tissue macrophages. The sensitivity of MetSig to the RA disease activity and the treatment effect were assessed experimentally and clinically.

Results: CDC42 hiCD14+ 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 CDC42 hiCD14+ 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 CDC42 hiCD14+ 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 CDC42 hiCD14+ cells discloses patients perceptive to the JAKi treatment.

Keywords: CD14+ cells; Rho-GTPases; arthritis; oxidative phosphorylation; proteasome; synovia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Rheumatoid*
  • Cytokines
  • Homeostasis
  • Inflammation
  • Mice
  • Proteasome Endopeptidase Complex*
  • rho GTP-Binding Proteins

Substances

  • Proteasome Endopeptidase Complex
  • rho GTP-Binding Proteins
  • Cytokines

Grants and funding

This work has been funded by grants from the Swedish Research Council (MB: 2017-03025 and 2017-00359), the Swedish Association Against Rheumatism (MB: R-566961, R-751351, and R-860371), the King Gustaf V:s 80-year Foundation (MB: FAI-2018-0519 and FAI-2020-0653), the Regional Agreement on Medical Training and Clinical Research Between the Western Götaland County Council and the University of Gothenburg (MB: ALFGBG-717681 and ALFGBG-965623; RP: ALFGBG-965012 and ALFGBG-926621), and the University of Gothenburg. The authors declare that the funding sources have no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.