ITGA5+ synovial fibroblasts orchestrate proinflammatory niche formation by remodelling the local immune microenvironment in rheumatoid arthritis
Zheng, Linli; Gu, Minghui; Li, Xiang; Hu, Xuantao; Chen, Chen; Kang, Yunze; Pan, Baiqi; Chen, Weishen; Xian, Guoyan; Wu, Xiaoyu; Li, Chengxin; Wang, Chao; Li, Zhiwen; Guan, Mingqiang; Zhou, Guanming; Mobasheri, Ali; Song, Weidong; Peng, Sui; Sheng, Puyi; Zhang, Ziji (2024-11-01)
BMJ Books
01.11.2024
Zheng, L., Gu, M., Li, X., Hu, X., Chen, C., Kang, Y., Pan, B., Chen, W., Xian, G., Wu, X., Li, C., Wang, C., Li, Z., Guan, M., Zhou, G., Mobasheri, A., Song, W., Peng, S., Sheng, P., & Zhang, Z. (2025). ITGA5+ synovial fibroblasts orchestrate proinflammatory niche formation by remodelling the local immune microenvironment in rheumatoid arthritis. Annals of the Rheumatic Diseases, 84(2), 232–252. https://doi.org/10.1136/ard-2024-225778
https://creativecommons.org/licenses/by-nc-nd/4.0/
© 2024 The Author(s). Published by Elsevier B.V. on behalf of European Alliance of Associations for Rheumatology (EULAR). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
https://creativecommons.org/licenses/by-nc-nd/4.0/
© 2024 The Author(s). Published by Elsevier B.V. on behalf of European Alliance of Associations for Rheumatology (EULAR). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
https://creativecommons.org/licenses/by-nc-nd/4.0/
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:oulu-202412197465
https://urn.fi/URN:NBN:fi:oulu-202412197465
Tiivistelmä
Abstract
Objectives:
To investigate the phenotypic heterogeneity of tissue-resident synovial fibroblasts and their role in inflammatory response in rheumatoid arthritis (RA).
Methods:
We used single-cell and spatial transcriptomics to profile synovial cells and spatial gene expressions of synovial tissues to identify phenotypic changes in patients with osteoarthritis, RA in sustained remission and active state. Immunohistology, multiplex immunofluorescence and flow cytometry were used to identify synovial fibroblasts subsets. Deconvolution methods further validated our findings in two cohorts (PEAC and R4RA) with treatment response. Cell coculture was used to access the potential cell-cell interactions. Adoptive transfer of synovial cells in collagen-induced arthritis (CIA) mice and bulk RNA sequencing of synovial joints further validate the cellular functions.
Results:
We identified a novel tissue-remodelling CD45–CD31–PDPN+ITGA5+ synovial fibroblast population with unique transcriptome of POSTN, COL3A1, CCL5 and TGFB1, and enriched in immunoregulatory pathways. This subset was upregulated in active and lympho-myeloid type of RA, associated with an increased risk of multidrug resistance. Transforming growth factor (TGF)-β1 might participate in the differentiation of this subset. Moreover, ITGA5+ synovial fibroblasts might occur in early stage of inflammation and induce the differentiation of CXCL13hiPD–1hi peripheral helper T cells (TPHs) from naïve CD4+ T cells, by secreting TGF-β1. Intra-articular injection of ITGA5+ synovial fibroblasts exacerbates RA development and upregulates TPHs in CIA mice.
Conclusions:
We demonstrate that ITGA5+ synovial fibroblasts might regulate the RA progression by inducing the differentiation of CXCL13hiPD–1hi TPHs and remodelling the proinflammatory microenvironments. Therapeutic modulation of this subpopulation could therefore be a potential treatment strategy for RA.
Objectives:
To investigate the phenotypic heterogeneity of tissue-resident synovial fibroblasts and their role in inflammatory response in rheumatoid arthritis (RA).
Methods:
We used single-cell and spatial transcriptomics to profile synovial cells and spatial gene expressions of synovial tissues to identify phenotypic changes in patients with osteoarthritis, RA in sustained remission and active state. Immunohistology, multiplex immunofluorescence and flow cytometry were used to identify synovial fibroblasts subsets. Deconvolution methods further validated our findings in two cohorts (PEAC and R4RA) with treatment response. Cell coculture was used to access the potential cell-cell interactions. Adoptive transfer of synovial cells in collagen-induced arthritis (CIA) mice and bulk RNA sequencing of synovial joints further validate the cellular functions.
Results:
We identified a novel tissue-remodelling CD45–CD31–PDPN+ITGA5+ synovial fibroblast population with unique transcriptome of POSTN, COL3A1, CCL5 and TGFB1, and enriched in immunoregulatory pathways. This subset was upregulated in active and lympho-myeloid type of RA, associated with an increased risk of multidrug resistance. Transforming growth factor (TGF)-β1 might participate in the differentiation of this subset. Moreover, ITGA5+ synovial fibroblasts might occur in early stage of inflammation and induce the differentiation of CXCL13hiPD–1hi peripheral helper T cells (TPHs) from naïve CD4+ T cells, by secreting TGF-β1. Intra-articular injection of ITGA5+ synovial fibroblasts exacerbates RA development and upregulates TPHs in CIA mice.
Conclusions:
We demonstrate that ITGA5+ synovial fibroblasts might regulate the RA progression by inducing the differentiation of CXCL13hiPD–1hi TPHs and remodelling the proinflammatory microenvironments. Therapeutic modulation of this subpopulation could therefore be a potential treatment strategy for RA.
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