Aberrant expression of USF2 in refractory rheumatoid arthritis and its regulation of proinflammatory cytokines in Th17 cells

Abstract

IL-17–producing Th17 cells are implicated in the pathogenesis of rheumatoid arthritis (RA) and TNF-α, a proinflammatory cytokine in the rheumatoid joint, facilitates Th17 differentiation. Anti-TNF therapy ameliorates disease in many patients with rheumatoid arthritis (RA). However, a significant proportion of patients do not respond to this therapy. The impact of anti-TNF therapy on Th17 responses in RA is not well understood. We conducted high-throughput gene expression analysis of Th17-enriched CCR6+CXCR3−CD45RA−CD4+T (CCR6+T) cells isolated from anti-TNF–treated RA patients classified as responders or nonresponders to therapy. CCR6+T cells from responders and nonresponders had distinct gene expression profiles. Proinflammatory signaling was elevated in the CCR6+T cells of nonresponders, and pathogenic Th17 signature genes were up-regulated in these cells. Gene set enrichment analysis on these signature genes identified transcription factor USF2 as their upstream regulator, which was also increased in nonresponders. Importantly, short hairpin RNA targetingUSF2in pathogenic Th17 cells led to reduced expression of proinflammatory cytokines IL-17A, IFN-γ, IL-22, and granulocyte-macrophage colony-stimulating factor (GM-CSF) as well as transcription factor T-bet. Together, our results revealed inadequate suppression of Th17 responses by anti-TNF in nonresponders, and direct targeting of the USF2-signaling pathway may be a potential therapeutic approach in the anti-TNF refractory RA.

Plasma interleukin-23 and circulating IL-17A+IFNγ+ ex-Th17 cells predict opposing outcomes of anti-TNF therapy in rheumatoid arthritis

“…Among alternative possibilities, TNF-α makes a contribution towards the differentiation of IL-17A producing Th17 cells [ 15 ] and subsequent synergy with IL-17A further increases the potency of TNF-α [ 8 ]. Pathogenic Th17 cells are a feature of RA, distinguished by a pro-inflammatory gene signature that includes elevated TNF transcript in non-responders [ 27 ] and is sustained by USF2 signalling pathways [ 28 ]. Importantly, TNF-α production by Th17 lineage cells increases as the cells trans-differentiate from classic Th17 cells, through IL-17A + IFNγ + ex-Th17 intermediaries, towards non-classical IFNγ + Th1 cell phenotypes, which concomitantly acquire a more pathogenic phenotype [ 29 ].…”

Bioflavonoid Robinin from Astragalus falcatus Lam. Mildly Improves the Effect of Metothrexate in Rats with Adjuvant Arthritis

“…Several studies have shown the increased concentration of IL-17A and/or Th17 in inflamed joints and blood of the patients suffering RA. It was recently shown a relation of IL-17A concentrations with the disease activity or joint damage [54,55]. Recent understanding of the etiopathogenesis of RA emphasized the role of the cytokine network in the initialization and development of the illness, which has bought a novel class of drugs for RA directly targeting cytokines [56].…”

Efficacy and safety of low-dose interleukin-2 in combination with methotrexate in patients with active rheumatoid arthritis: a randomized, double-blind, placebo-controlled phase 2 trial

“…4 ). 36 , 37 Inflammation associated cytokines or other soluble factors in patient serum, including IL-2, IL-6, IL-17A, IL-21 TNF-α, IFN-γ, sCD25, IL-4, IL-12, TGF-β, and CXCL13, were determined by ELISA kits (MultiSciences, Hangzhou, China), following instructions from the manufacturer.…”