Background/Purpose: Combination of IFN-stimulated genes known as IFN signature, helps to predict disease activity and treatment response in several autoimmune diseases, including rheumatoid arthritis (RA). Response to persistent IFNg stimulation demands metabolic adaptation of a cell by switching glucose metabolism from the tricarboxylic acid cycle (TCA) to the pentose phosphate pathway (PPP) that dramatically increases glucose intake. Fructose-2,6-biphosphatase 3 coded by PFKFB3, is the rate-limiting regulator of glucose metabolism suppressed in leukocytes of RA patients.

Objectives. To study effect of anti-rheumatic treatment on the cellular energy metabolism of CD14⁺ mononuclear cells and its connection to the CD14+ cell phenotype and IFNg signaling.

Methods: Blood CD14⁺ cells were sorted from the randomly recruited 59 RA patients (mean age 59.6y, DD 13.8y), activated with LPS for 2h and submitted to RNA sequencing (RNAseq, IluminaNextseq). By actual DMARD treatment, the patients were divided into those who had no DMARDs (n=9), methotrexate±biologics (MTX, n=26) and JAK-inhibitors (JAKi, n=24). Differentially expressed genes (DEGs) between the groups were identified by DESeq2 (Bioconductor package, R-studio). IFN signature genes (ISG)(1) were analyzed in relation to the transcriptomic profile behind the cellular energy metabolism and DMARD treatment.

Results: Treatment with MTX and JAKi made a significant and opposing contribution to the transcriptomic of energy metabolism in CD14⁺ cells. MTX-treated patients had significantly higher levels of PFKFB3 (p=0.042) and PGAM1 compared to those with no DMARDs, which reverted aerobic glycolysis by increasing expression of the pyruvate dehydrogenase complex proteins PDHA1, PHDX and PDK3 and decreasing PPP enzymes PGLS, RPIA and TKT. In contrast, JAKi-treated patients had suppressed PFKFB3 compared to MTX-treated (p=1.32e-8). This significantly activated glycolysis downstream of PFKFB3 and shunted it into PPP by significantly inducing expression of G6PD, PGLS, and glucose transporter SLC2A1.

These differences in glucose metabolism were linked to divergent phenotype of CD14⁺ cells being short-lived CD14^intCD11c^hi cells and IL6 producing in MTX-treated patients and long-lived mature CD14^hiCD11b^hiCX3CR1^hi cells and IFNg producing in JAKi-treated patients. CD14⁺ cells of JAKi-treated patients expressed low levels of STAT1 and ISGs compared to MTX-treated patients.

Conclusion: DMARD treatment has divergent effect on glycolysis of CD14⁺ cells, acting through modulation of PFKFB3. This has a significant impact on the phenotype of CD14⁺ cells and their inflammatory ability.

« Back to ACR Convergence 2022

ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-rheumatic-treatment-modulates-expression-of-the-glycolytic-enzyme-pfkfb3-in-cd14-monocytes-of-patients-with-rheumatoid-arthritis-which-contributes-to-dissimilarities-of-the-ifn-signature/