Metabolic signature and proteasome activity controls synovial migration ofCDC42hiCD14+cells in rheumatoid arthritis

Abstract

SummaryObjectiveActivation 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 in rheumatoid arthritis (RA) and how JAK inhibition mitigates these effects.MethodsCD14+cells of 136 RA patients were characterized by RNA-sequencing, and cytokine measurement to identify biological processes and transcriptional regulators specific forCDC42hiCD14+cells, which were summarized in a metabolic signature. 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 ofCDC42hisynovial tissue macrophages. Sensitivity of the metabolic signature to the RA disease activity and treatment effect was assessed experimentally and clinically.ResultsCDC42hiCD14+cells carried the metabolic signature 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 ofCDC42hiCD14+and synovial macrophages marked with the metabolic signature revealed the important role of the interferon-rich environment and immunoproteasome expression in homeostasis of these pathogenic macrophages. TheCDC42hiCD14+cells were targeted by JAK-inhibitors and responded with downregulation of immunoproteasome and MHC-II molecules, which disintegrated the immunological synapse, reduced cytokine production and alleviated arthritis.ConclusionThis study shows that the CDC42-related metabolic signature identifies the antigen-presenting CD14+cells that migrate to joints to coordinate autoimmunity. Accumulation ofCDC42hiCD14+cells disclose patients perceptive to JAKi treatment.