Session Type: Poster Session (Tuesday)
Session Time: 9:00AM-11:00AM
Background/Purpose: Background: A substantial proportion of Rheumatoid Arthritis patients do not respond to treatment and only a small proportion achieve sustained disease remission. We showed previously that human synovial tissue macrophages (STMs) are heterogeneous; and a sub-population of CD206+MertK+ positive STMs predominates in RA patients in sustained remission as compared to patients with active RA. Their surface receptors, e.g. MerTK, and distinct transcriptome suggest that they may play a role in re-enforcing joint homeostasis (1). Thus, we hypothesise that activation of CD206+MerTK+ human synovial tissue macrophages contributes to the resolution of inflammation.
Objectives: We aimed to investigate whether activation of MerTK in STM sub-population promotes an anti-inflammatory environment in the synovium.
Methods: Methods: Using flow cytometric techniques and with a specific antibody panel design (1), STMs from digested RA synovial biopsies were phenotyped and/or harvested for functional studies. The study included patients with active disease and patients in remission (DAS28 ESR< 2.6 and power doppler negative). After excluding all other cell types, macrophages were gated based on the expression of CD64 and CD11b (CD45posCD64posCD11bposHLA-DRpos) (1). Two distinct subpopulations: CD206+MerTK+ and CD206-MerTK- were sorted and cultured on a collagen coated 96-well plate at 1000 cells per well in the presence of with LPS (10ng/ml) ± Gas 6, a MerTK ligand (100ng/ml), for 24h. Cytokine production was measured using a high sensitivity UPLEX assay. To test the role of MerTK expressing macrophages on the activation of synovial fibroblasts, a trans-well membrane coculture system was used. Macrophages were pre-treated with LPS (1ng/ml) ± MertK inhibitor (UNC1062, 100um-250um) for 4 and 2 hours respectively, and then co-cultured with fibroblasts for 48hours. MMPs production were measured by multiplex.
Results: Results: As previously shown (1), RA patients in sustained remission have a majority CD206+MerTK+ STMs, whilst patients with active RA show an increased number of CD206–MerTK– macrophages. The percentage of CD206+MerTK+ macrophages negatively correlated with the disease activity score in RA. Stimulation of FACS-Aria sorted CD206+MerTK+ and CD206–MerTK– macrophages with TLR4 ligand induced a different cytokine pattern: the CD206–MerTK– macrophages mostly produced TNF, IL-6 and IL-1b while CD206+MerTK+ produced IL-10. Inhibition of MerTK in macrophages increased the production of MMP1 and MMP3 by synovial fibroblasts in the co-culture system.
Conclusion: Conclusion: CD206+MERTK+ macrophages, which predominate in RA patients in remission, have Gas6-mediated negative feedback mechanism limiting inflammatory cytokine production and activation of synovial fibroblasts. Thus, Gas6/MerTK pathway in synovial tissue macrophages could drive the resolution of inflammation and synovial tissue homeostasis.
- Elmesmari A et al., Synovial tissue of RA patients in remission contains a unique population of regulatory macrophages. Annals of the Rheumatic Diseases, 2017;76 (Suppl2) 138-139.
To cite this abstract in AMA style:Finlay S, Alivernini S, Elmesmari A, Tolusso B, Petricca L, Di Mario C, Capacci A, Filer A, Ferraccioli G, McInnes I, Gremese E, Kurowska-Stolarska M. Presence of the MerTK Receptor on Human Synovial Tissue Macrophages Lowers Inflammatory Cytokine Production and Activation of the MerTK+CD206+ Subpopulation Limits the Inflammatory Response of Synovial Fibroblasts [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/presence-of-the-mertk-receptor-on-human-synovial-tissue-macrophages-lowers-inflammatory-cytokine-production-and-activation-of-the-mertkcd206-subpopulation-limits-the-inflammatory-response-of-synovia/. Accessed October 22, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/presence-of-the-mertk-receptor-on-human-synovial-tissue-macrophages-lowers-inflammatory-cytokine-production-and-activation-of-the-mertkcd206-subpopulation-limits-the-inflammatory-response-of-synovia/