{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T21:10:55Z","timestamp":1786741855858,"version":"build-2736575974"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T00:00:00Z","timestamp":1702512000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Inflammatory-erosive arthritis is exacerbated by dysfunction of joint-draining popliteal lymphatic vessels (PLVs). Synovial mast cells are known to be pro-inflammatory in rheumatoid arthritis (RA). In other settings they have anti-inflammatory and tissue reparative effects. Herein, we elucidate the role of mast cells on PLV function and inflammatory-erosive arthritis in tumor necrosis factor transgenic (TNF-tg) mice that exhibit defects in PLVs commensurate with disease progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole mount immunofluorescent microscopy, toluidine blue stained histology, scanning electron microscopy, and <jats:italic>in silico<\/jats:italic> bioinformatics were performed to phenotype and quantify PLV mast cells. Ankle bone volumes were assessed by \u03bcCT, while corresponding histology quantified synovitis and osteoclasts. Near-infrared indocyanine green imaging measured lymphatic clearance as an outcome of PLV draining function. Effects of genetic MC depletion were assessed via comparison of 4.5-month-old WT, TNF-tg, MC deficient <jats:italic>Kit<jats:sup>W-sh\/W-sh<\/jats:sup><\/jats:italic> (cKit<jats:sup>-\/-<\/jats:sup>), and TNF-tg x cKit<jats:sup>-\/-<\/jats:sup> mice. Pharmacological inhibition of mast cells was assessed by treating TNF-tg mice with placebo or cromolyn sodium (3.15mg\/kg\/day) for 3-weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PLVs are surrounded by MCT<jats:sup>+<\/jats:sup>\/MCPT1<jats:sup>+<\/jats:sup>\/MCPT4<jats:sup>+<\/jats:sup> mast cells whose numbers are increased 2.8-fold in TNF-tg mice. The percentage of peri-vascular degranulating mast cells was inversely correlated with ICG clearance. A population of MCT<jats:sup>+<\/jats:sup>\/MCPT1<jats:sup>-<\/jats:sup>\/MCPT4<jats:sup>-<\/jats:sup> mast cells were embedded within the PLV structure. <jats:italic>In silico<\/jats:italic> single-cell RNA-seq (scRNAseq) analyses identified a population of PLV-associated mast cells (marker genes: <jats:italic>Mcpt4, Cma1, Cpa3, Tpsb2, Kit, Fcer1a &amp;amp; Gata2<\/jats:italic>) with enhanced TGF\u03b2-related signaling that are phenotypically distinct from known MC subsets in the <jats:italic>Mouse Cell Atlas<\/jats:italic>. cKit<jats:sup>-\/-<\/jats:sup> mice have greater lymphatic defects than TNF-tg mice with exacerbation of lymphatic dysfunction and inflammatory-erosive arthritis in TNF-tg x cKit<jats:sup>-\/-<\/jats:sup> vs. TNF-Tg mice. Cromolyn sodium therapy stabilized PLV mast cells, increased TNF-induced bone loss, synovitis, and osteoclasts, and decreased ICG clearance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Mast cells are required for normal lymphatic function. Genetic ablation and pharmacological inhibition of mast cells exacerbates TNF-induced inflammatory-erosive arthritis with decreased lymphatic clearance. Together, these findings support an inflammatory role of activated\/degranulated peri-PLV mast cells during arthritic progression, and a homeostatic role of intra-PLV mast cells, in which loss of the latter dominantly exacerbates arthritis secondary to defects in joint-draining lymphatics, warranting investigation into specific cellular mechanisms.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1275871","type":"journal-article","created":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T16:41:22Z","timestamp":1702572082000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Distinct mast cell subpopulations within and around lymphatic vessels regulate lymph flow and progression of inflammatory-erosive arthritis in TNF-transgenic mice"],"prefix":"10.3389","volume":"14","author":[{"given":"Yue","family":"Peng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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