Background: Psoriatic arthritis (PsA) is a chronic, heterogeneous autoinflammatory disease characterized by inflammatory involvement of the joints and entheses. The interleukin-17/interleukin-22 axis and persistent inflammation play a central role in the pathogenesis of disease. We hypothesized that PsA is characterized by altered lipid-mediator–associated regulation at the cellular level.

Objectives: To further study the lipid alternation, we aimed to (i) comprehensively map immune cell composition and metabolic marker expression in PsA compared with healthy controls (HC), (ii) assess longitudinal changes following anti-IL-17 biological therapy, and (iii) integrate immunophenotypic, metabolic, inflammatory, and clinical parameters to define mechanisms underlying treatment response.

Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 17 patients with PsA and 11 age- and sex-matched healthy controls and analyzed using high-dimensional mass cytometry (CyTOF). Immune cell populations were identified using unsupervised clustering followed by biologically informed refinement. Cross-sectional comparisons between HC and PsA were performed, followed by paired before-and-after analyses in PsA patients receiving IL-17–targeted biological therapy. Marker panels included molecules involved in glycolysis (GLUT1/SLC2A1, HK1), fatty-acid metabolism (ACAC/ACC1, CPT1A), amino-acid metabolism (ASS1), immune activation (HLA-DR, CD38), IL-17 signaling (IL-17A, IL-17RA, IL-7R), and resolution pathways (ALX/FPR2). Serum Lipoxin A4 levels were quantified using Enzyme-Linked Immunosorbent Assay (ELISA) to assess systemic resolution mediator activity. Associations between immune/metabolic markers and clinical parameters (DAS28-CRP, tender and swollen joint counts, CRP, ESR, VAS, and SJC) were evaluated using Spearman correlation analyses.

Results: Compared with healthy controls, PsA patients exhibited sustained immune activation with selective remodeling of immune compartments. Naïve B cells were significantly reduced, memory B-cell subsets were altered, and monocyte-like dendritic cells (DC3) were expanded, while most major T-cell, monocyte, and dendritic subsets showed preserved overall frequencies. Despite this apparent cellular stability, PsA was characterized by marked alterations in immunometabolic regulation across multiple immune lineages. Notably, acetyl-CoA carboxylase-1 (ACC1), a key enzyme controlling de novo lipogenesis, was significantly reduced in myeloid dendritic cell subsets in PsA compared with HC, indicating impaired lipogenic programming in antigen-presenting cells. Fatty-acid oxidation–related pathways, reflected by CPT1A expression, and amino-acid metabolism (ASS1) showed subset-specific dysregulation, highlighting a metabolic imbalance favoring inflammatory persistence. Glycolytic markers (GLUT1 and HK1) correlated positively with clinical disease activity measures, linking metabolic activation to inflammatory burden. Following IL-17 blockade, paired longitudinal analyses revealed selective but biologically meaningful immune remodeling rather than global immune suppression. Frequencies of inflammatory effector populations, including CD8 effector memory T cells and early natural killer (CD56^bright-like) cells, were reduced, while trends toward restoration were observed in late NK (CD56^dim-like) and central memory CD4 T-cell compartments. Although several changes did not reach statistical significance, consistent directional trends across paired samples suggested coordinated immunological rebalancing. Importantly, IL-17 inhibition was associated with modulation of immunometabolic markers. ACC1 expression showed partial normalization in specific immune subsets, while IL-17–related marker distributions across T-cell subsets shifted toward a less inflammatory profile. The pro-resolving lipid mediator receptor ALX/FPR2 demonstrated increased expression across monocyte, late NK cells, and T-cell compartments in post-treatment samples. This cellular upregulation was paralleled by a significant increase in circulating serum Lipoxin A4 levels after therapy, providing functional evidence of restored resolution pathways. Correlation analyses further supported an integrated immunometabolic-clinical axis in PsA. Metabolic enzymes (ACC1, CPT1A, ASS1), IL-17 signaling markers, and ALX/FPR2 expression showed significant associations with disease activity indices, inflammatory markers, and patient-reported outcomes, underscoring their relevance to clinical disease expression.

Conclusions: Our findings support a model in which chronic inflammation in PsA is maintained by selective immune-cell remodeling coupled with dysregulated lipid-mediator–associated immunometabolic pathways rather than by broad immune expansion alone. IL-17 blockade induces targeted immunological and metabolic reprogramming, accompanied by reactivation of pro-resolving lipid mediator signaling. These results highlight immunometabolic pathways, particularly fatty-acid metabolism and resolution mechanisms, as promising biomarkers and therapeutic targets for patient stratification and treatment monitoring in PsA. This model is also the first to validate the use of mass cytometry as a study technique for Immunometabolic Reprogramming

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.