Background/Purpose: While Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA) share many features, they are distinct in clinical presentation and molecular profile. As monocytes are crucial innate effector cells, we investigate metabolic reprogramming of circulating monocytes in RA and PsA, and pathways involved in activation, circadian rhythm and mitochondrial dynamics.

Methods: PBMCs and CD14⁺ monocytes were isolated from RA and PsA patients. Frequency of monocyte subsets and immune/metabolism markers (PDL-1, HIF1a, pS6, TLR2 and pAKT) on specific subsets were assessed by flow cytometry. Metabolic analysis was performed on basal and LPS stimulated monocytes by RT-PCR, Seahorse-XFe-technology and mitotracker assays. In parallel, genes involved in circadian rhythm (BMAL1, PER1, PER2) and mitochondrial fission and fusion (DRP1, MFN1) and related effectors (RORα and NFIL3) were assessed by RT-PCR.

Results: Baseline ECAR following LPS stimulation was induced, with minimal effect observed for OCR, resulting in a significant shift of RA and PsA monocytes towards glycolysis (p< 0.05). A significant reduction in max respiratory capacity and ATP synthesis was also observed for PsA vs RA (all p< 0.05). Differential expression of PDL-1, pS6 and HIF1α were observed between RA and PsA monocytes, with inverse expression observed between classical and intermediate sub-populations. LPS modulated key metabolic genes HIF1α (p< 0.001) and NDufB5 (p< 0.05), an effect more prominent in RA monocytes. Supporting mitochondrial dysfunction in RA, LPS stimulation induced mitochondrial fission regulator DRP1 in RA (p< 0.0001), but not PsA. For circadian rhythm genes, LPS-stimulation inhibited BMAL1(p< 0.05) and PER1 (p< 0.001) in both RA and PsA, with reduction in PER2 only observed in PsA (p< 0.05). Finally, downstream effectors RORα and NFIL3 were increased with LPS in RA monocytes, with no effect observed for PsA.

Conclusion: RA and PsA CD14+ monocytes display a shift towards a glycolytic phenotype. Metabolic/immune markers are differentially expressed between RA and PsA monocytes, expression of which are inversed in classical vs intermediate monocytes. Altered regulation of genes involved in circadian rhythm suggest differences in the cellular clock, and effect that was more pronounced in RA compared to PsA monocytes. This was paralleled by altered mitochondrial dynamics, with significant induction of mitochondrial fission regulator DRP1 in RA monocytes. Taken together, this data, supports differential metabolic dysregulation and activation of RA and PsA monocytes, effects that may involve changes in the cellular clock, inducing monocyte pathogenic mechanisms.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/differential-metabolic-profiles-activation-and-circadian-dynamics-in-rheumatoid-arthritis-and-psoriatic-arthritis-circulatory-monocytes/