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 targeting USF2 in 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.

• Authors: Dan Hu, Emily C Tjon, Karin M Andersson, Gabriela M Molica, Minh C Pham, Brian Healy, Gopal Murugaiyan, Nathalie Pochet, Vijay K Kuchroo, Maria I Bokarewa, Howard L Weiner
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 48 Pg. 30639-30648 (12 01 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 33203678 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 the Author(s). Published by PNAS.

Chemical References

• Antirheumatic Agents
• Biomarkers
• CCR6 protein, human
• CD4 Antigens
• CXCR3 protein, human
• Cytokines
• Inflammation Mediators
• RNA, Small Interfering
• Receptors, CCR6
• Receptors, CXCR3
• Tumor Necrosis Factor-alpha
• USF2 protein, human
• Upstream Stimulatory Factors

Topics

• Antirheumatic Agents (pharmacology, therapeutic use)
• Arthritis, Rheumatoid (drug therapy, etiology, metabolism, pathology)
• Biomarkers
• CD4 Antigens (metabolism)
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• Cytokines (metabolism)
• Gene Expression
• Gene Expression Profiling
• Humans
• Inflammation Mediators (metabolism)
• RNA, Small Interfering (genetics)
• Receptors, CCR6 (metabolism)
• Receptors, CXCR3 (metabolism)
• Signal Transduction (drug effects)
• Th17 Cells (immunology, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• Upstream Stimulatory Factors (genetics)