Dataset Information

Metabolic signature and proteasome activity controls synovial migration of CDC42^hiCD14⁺ cells in rheumatoid arthritis.

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.

SUBMITTER: Malmhall-Bah E

PROVIDER: S-EPMC10469903 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Metabolic signature and proteasome activity controls synovial migration of <i>CDC42<sup>hi</sup></i>CD14<sup>+</sup> cells in rheumatoid arthritis.

Malmhäll-Bah Eric E Andersson Karin M E KME Erlandsson Malin C MC Silfverswärd Sofia T ST Pullerits Rille R Bokarewa Maria I MI

Frontiers in immunology 20230817

<h4>Objective</h4>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.<h4>Methods</h4>CD14<sup>+</sup> cells of 136 RA patients were characterized by RNA sequencing and cytokine measurement to identify biological processes and transcriptional regulator ...[more]

PMID: 37662900

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Project description:Dendritic cells (DC) have a key role in the initiation and progression of inflammatory arthritis (IA). In this study, we identified a DC population that derive from monocytes, characterized as CD209/CD14+ DC, expressing classical DC markers (HLADR, CD11c) and the Mo-DC marker (CD209), while also retaining the monocytic marker CD14. This CD209/CD14+ DC population is present in the circulation of Healthy Control (HC), with increased frequency in Rheumatoid Arthritis (RA) and Psoriatic arthritic (PsA) patients. We demonstrate, for the first time, that circulatory IA CD209/CD14+ DC express more cytokines (IL1β/IL6/IL12/TNFα) and display a unique chemokine receptor expression and co-expression profiles compared to HC. We demonstrated that CD209/CD14+ DC are enriched in the inflamed joint where they display a unique inflammatory and maturation phenotype, with increased CD40 and CD80 and co-expression of specific chemokine receptors, displaying unique patterns between PsA and RA. We developed a new protocol of magnetic isolation and expansion for CD209+ DC from blood and identified transcriptional differences involved in endocytosis/antigen presentation between RA and PsA CD209+ DC. In addition, we observed that culture of healthy CD209+ DC with IA synovial fluid (SF), but not Osteoarthritis (OA) SF, was sufficient to induce the development of CD209/CD14+ DC, leading to a poly-mature DC phenotype. In addition, differential effects were observed in terms of chemokine receptor and chemokine expression, with healthy CD209+ DC displaying increased expression/co-expression of CCR6, CCR7, CXCR3, CXCR4 and CXCR5 when cultured with RA SF, while an increase in the chemokines CCR3, CXCL10 and CXCL11 was observed when cultured with PsA SF. This effect may be mediated in part by the observed differential increase in chemokines expressed in RA vs PsA SF. Finally, we observed that the JAK/STAT pathway, but not the NF-κB pathway (driven by TNFα), regulated CD209/CD14+ DC function in terms of activation, inflammatory state, and migratory capacity. In conclusion, we identified a novel CD209/CD14+ DC population, which is active in the circulation of RA and PsA, an effect potentiated once they enter the joint. Furthermore, we demonstrated that JAK/STAT inhibition can be used as a therapeutic strategy to decrease the inflammatory state of the pathogenic CD209/CD14+ DC.

Project description:The presence of anti-citrullinated protein/peptide antibodies (ACPA) and epitope spreading across the target autoantigens is a unique feature of rheumatoid arthritis (RA). ACPA are present in the peripheral blood for several years prior to the onset of arthritis and clinical classification of RA. ACPA recognize multiple citrullinated proteins, including histone H3 (H3). Intracellular citrullination of H3 in neutrophils and T cells is known to regulate immune cell function by promoting neutrophil extracellular trap formation and citrullinated autoantigen release as well as regulating the Th2/Th17 T cell phenotypic balance. However, the roles of H3 citrullination in other immune cells are not fully elucidated. We aimed to explore H3 citrullination and cytokine/metabolomic signatures in peripheral blood immune cells from subjects prior to and after the onset of RA, at baseline and in response to ex vivo toll-like receptor (TLR) stimulation. Here, we analyzed 13 ACPA (+) subjects without arthritis but at-risk for future development of RA, 14 early RA patients, and 13 healthy controls. We found significantly elevated H3 citrullination in CD14hi monocytes, as well as CD1c+ dendritic cells and CD66+ granulocytes. Unsupervised analysis identified two distinct subsets in CD14hi monocytes characterized by H3 modification and unique cytokine/metabolomic signatures. CD14hi monocytes with elevated TLR-stimulated H3 citrullination were significantly increased in ACPA (+) at-risk subjects. These cells were skewed to produce TNFα, MIP1β, IFNα, and partially IL-12. Additionally, they demonstrate peptidyl arginine deiminase 4 (PAD4) mediated upregulation of the glycolytic enzyme PFKFB3. These CD14hi monocytes with elevated H3 citrullination morphologically formed monocyte extracellular traps (METs). Taken together, dysregulated PAD4-driven cytokine production as well as MET formation in CD14hi monocytes in ACPA (+) at-risk subjects likely plays an important role in the development of RA via promoting and perpetuating inflammation and generation of citrullinated autoantigens.

Dataset Information

Metabolic signature and proteasome activity controls synovial migration of CDC42^hiCD14⁺ cells in rheumatoid arthritis.

Objective

Methods

Results

Conclusion

Publications

Metabolic signature and proteasome activity controls synovial migration of <i>CDC42<sup>hi</sup></i>CD14<sup>+</sup> cells in rheumatoid arthritis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Metabolic signature and proteasome activity controls synovial migration of CDC42hiCD14+ cells in rheumatoid arthritis.

Objective

Methods

Results

Conclusion

Publications

Metabolic signature and proteasome activity controls synovial migration of <i>CDC42<sup>hi</sup></i>CD14<sup>+</sup> cells in rheumatoid arthritis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Metabolic signature and proteasome activity controls synovial migration of CDC42^hiCD14⁺ cells in rheumatoid arthritis.