Aberrant expression of USF2 in refractory rheumatoid arthritis and its regulation of proinflammatory cytokines in Th17 cells
| Autor: | Howard L. Weiner, Maria I. Bokarewa, Gopal Murugaiyan, Karin M. E. Andersson, Dan Hu, Minh C. Pham, Gabriela M. Molica, Nathalie Pochet, Brian C. Healy, Vijay K. Kuchroo, Emily C. Tjon |
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| Rok vydání: | 2020 |
| Předmět: |
CD4-Positive T-Lymphocytes
Receptors CCR6 rheumatoid arthritis 0301 basic medicine Receptors CXCR3 USF2 Gene Expression chemical and pharmacologic phenomena C-C chemokine receptor type 6 Proinflammatory cytokine Arthritis Rheumatoid Pathogenesis Small hairpin RNA 03 medical and health sciences Immunology and Inflammation 0302 clinical medicine Gene expression medicine Humans RNA Small Interfering proinflammatory Transcription factor Multidisciplinary Tumor Necrosis Factor-alpha business.industry Gene Expression Profiling hemic and immune systems Biological Sciences medicine.disease 030104 developmental biology Antirheumatic Agents 030220 oncology & carcinogenesis Rheumatoid arthritis CD4 Antigens Cancer research Cytokines Th17 Cells Upstream Stimulatory Factors Th17 Inflammation Mediators business Biomarkers Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance Identifying signaling pathways contributing to resistance to anti-TNF therapy in rheumatoid arthritis is crucial for the development of new therapeutic strategies for refractory rheumatoid arthritis. Th17 cells, a subset of proinflammatory CD4+ T cells, are implicated in the pathogenesis of the disease. We analyzed the gene expression profiles of Th17-enriched CD4+ T cells in anti-TNF–treated patients with rheumatoid arthritis and found that the elevated expression levels of transcription factor USF2 in anti-TNF refractory patients were associated with increased proinflammatory signaling of Th17 cells. USF2-knockdown experiments in Th17 cells revealed that USF2 promotes the pathogenicity of Th17 cells. These findings have implications for the development of new therapeutic strategies for refractory rheumatoid arthritis. 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. |
| Databáze: | OpenAIRE |
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