Objective

AUTHOR=Malmhäll-Bah Eric , Andersson Karin M.E. , Erlandsson Malin C. , Silfverswärd Sofia T. , Pullerits Rille , Bokarewa Maria I. TITLE=Metabolic signature and proteasome activity controls synovial migration of CDC42hiCD14+ cells in rheumatoid arthritis JOURNAL=Frontiers in Immunology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1187093 DOI=10.3389/fimmu.2023.1187093 ISSN=1664-3224 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.