Figure - available from: Journal of Experimental Medicine (JEM)
This content is subject to copyright.
Topography of recruited neutrophils during AIA: Onset-specific clustering in the synovial lining and interaction with mBSA-laden lining macrophages. (A and B) Confocal images of murine synovia during AIA in CX3CR1-eGFP Ly6G-tdTomato double reporter mice show that neutrophils cluster in the synovial lining niche at the onset: 6 h large overview (A) and 4 h anterior synovium ROI (B) have uniform distribution at day 2 (peak of inflammation, middle panel) and form localized swarms at day 7 (resolution of inflammation, bottom panel). CD68, cyan; CX3CR1, orange; VSIG4, magenta; Ly6G-tdTomato, green; nuclei, gray; scale bar = 300 and 50 µm in the entire mouse knee cross-section and ROIs, respectively. (C) Respective quantification of neutrophil position within the anterior synovium of the whole knee cross-sections as in A: neutrophil distance to the lining at the onset (6 h), peak (day 2), and resolution (day 7) of AIA presented in violin plots. Each violin plot represents three mice combined with two to three sections at different positions in the knee quantified, median and interquartile range indicated. Total quantifications: N = 3; n = 2–3; N indicates mouse group size, n the number of sections per mouse; samples from four independent experiments. P values by Kolmogorov–Smirnov comparison: ****, P < 0.0001. CL, cruciate ligaments; F, femur; FP, fat pad; M, meniscus; SC, synovial cavity. (D) Lining macrophages (L.MΦ) exhibiting higher mBSA uptake interact with more neutrophils (PMN) compared with the macrophages with lower mBSA uptake (whole anterior lining quantified on two different sections of a single mouse at 4 h p.c.; P value by Wilcoxon rank–sum test: *, P < 0.05). (E) Confocal image of the anterior synovium 4 h after injection of fluorescently labeled mBSA shows recruited neutrophils interacting with mBSA-laden lining macrophages (CD68, cyan; VSIG4, magenta; mBSA, yellow; neutrophil CD177, green; colocalization of VSIG4 and mBSA, white; scale bar = 10 µm). FP, fat pad; SC, synovial cavity.
Source publication
The first immune-activating changes within joint resident cells that lead to pathogenic leukocyte recruitment during articular inflammation remain largely unknown. In this study, we employ state-of-the-art confocal microscopy and image analysis in a systemic, whole-organ, and quantitative way to present evidence that synovial inflammation begins wi...
Citations
... A rapid vascular leak localized to joints, particularly distal joints, accompanies and promotes subsequent joint damage in the K/BxN serum-induced arthritis (SIA) model that mimics clinical and immunological features of the effector phase of human inflammatory arthritis (29,38). Similarly, in antigen-induced arthritis, IC entry into the joint space and phagocytosis by synovial lining macrophages initiates neutrophil recruitment and articular inflammation (39). ...
Due to optimised treatment strategies and the availability of new therapies during the last decades, formerly devastating chronic inflammatory diseases such as rheumatoid arthritis or systemic sclerosis (SSc) have become less menacing. However, in many patients, even state-of-the-art treatment cannot induce remission. Moreover, the risk for flares strongly increases once anti-inflammatory therapy is tapered or withdrawn, suggesting that underlying pathological processes remain active even in the absence of overt inflammation. It has become evident that tissues have the ability to remember past encounters with pathogens, wounds and other irritants, and to react more strongly and/or persistently to the next occurrence. This priming of the tissue bears a paramount role in defence from microbes, but on the other hand drives inflammatory pathologies (the Dr Jekyll and Mr Hyde aspect of tissue adaptation). Emerging evidence suggests that long-lived tissue-resident cells, such as fibroblasts, macrophages, long-lived plasma cells and tissue-resident memory T cells, determine inflammatory tissue priming in an interplay with infiltrating immune cells of lymphoid and myeloid origin, and with systemically acting factors such as cytokines, extracellular vesicles and antibodies. Here, we review the current state of science on inflammatory tissue priming, focusing on tissue-resident and tissue-occupying cells in arthritis and SSc, and reflect on the most promising treatment options targeting the maladapted tissue response during these diseases.
Regulatory T cells (Tregs) are a very specialized subset of T lymphocytes: their main function is controlling immune responses during inflammation. T-regs involvement in autoimmune and immune-mediated rheumatic diseases is well-described. Here, we critically review the up-to-date literature findings on the role of Tregs in spondyloarthropathies, particularly in ankylosing spondylitis (AS), a polygenic inflammatory rheumatic disease that preferentially affects the spine and the sacroiliac joints. Genetics discoveries helped in elucidating pathogenic T-regs gene modules and functional involvement. We highlight T-regs tissue specificity as crucial point, as T-regs might have a distinct epigenomic and molecular profiling depending on the different site of tissue inflammation. Furthermore, we speculate about possible therapeutic interventions targeting, or enhancing, Treg cells in spondyloarthropathies.
