Cytokine-directed cellular cross-talk imprints synovial pathotypes in rheumatoid arthritis.

Introduction: Structural reorganisation of the synovium with expansion of fibroblast-like synoviocytes (FLS) and influx of immune cells is a hallmark of rheumatoid arthritis (RA). Activated FLS are increasingly recognised as a critical component driving synovial tissue remodelling by interacting with immune cells resulting in distinct synovial pathotypes of RA.
Methods: Automated high-content fluorescence microscopy of co-cultured cytokine-activated FLS and autologous peripheral CD4 ⁺ T cells from patients with RA was established to quantify cell-cell interactions. Phenotypic profiling of cytokine-treated FLS and co-cultured T cells was done by flow cytometry and RNA-Seq, which were integrated with publicly available transcriptomic data from patients with different histological synovial pathotypes. Computational prediction and knock-down experiments were performed in FLS to identify adhesion molecules for cell-cell interaction.
Results: Cytokine stimulation, especially with TNF-α, led to enhanced FLS-T cell interaction resulting in cell-cell contact-dependent activation, proliferation and differentiation of T cells. Signatures of cytokine-activated FLS were significantly enriched in RA synovial tissues defined as lymphoid-rich or leucocyte-rich pathotypes, with the most prominent effects for TNF-α. FLS cytokine signatures correlated with the number of infiltrating CD4 ⁺ T cells in synovial tissue of patients with RA. Ligand-receptor pair interaction analysis identified ICAM1 on FLS as an important mediator in TNF-mediated FLS-T cell interaction. Both, ICAM1 and its receptors were overexpressed in TNF-treated FLS and co-cultured T cells. Knock-down of ICAM1 in FLS resulted in reduced TNF-mediated FLS-T cell interaction.
Conclusion: Our study highlights the role of cytokine-activated FLS in orchestrating inflammation-associated synovial pathotypes providing novel insights into disease mechanisms of RA.
Competing Interests: Competing interests: MB reports about personal fees from Eli-Lilly and received grants from Galapagos, DA received grants and consulting fees from AbbVie, Amgen, Lilly, Merck, Novartis, Pfizer, Roche and Sandozand is an editorial board member of Annals of the Rheumatic Diseases, JSS reports about grants, consulting and personal fees from AbbVie, Astra-Zeneca, Lilly, Novartis, Amgen, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung and UCB and is editor-in-chief of Annals of the Rheumatic Diseases. ES reports speaker fees from Eli-Lilly and supports for attendance of meetings from Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim and Astra Zeneca. CP and is an editorial board member of Annals of the Rheumatic Diseases. The authors CP and MJL are named inventors on a patent application (no. GB 2100821.4), submitted by Queen Mary University of London, that covers methods used to select treatments in rheumatoid arthritis. All other authors declare no competing interests.
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