Distinct mast cell subpopulations within and around lymphatic vessels regulate lymph flow and progression of inflammatory-erosive arthritis in TNF-transgenic mice
ObjectiveInflammatory-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 eluci...
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| Format: | Article |
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Frontiers Media S.A.
2023-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1275871/full |
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| author | Yue Peng Yue Peng H. Mark Kenney H. Mark Kenney Karen L. de Mesy Bentley Karen L. de Mesy Bentley Lianping Xing Lianping Xing Christopher T. Ritchlin Christopher T. Ritchlin Edward M. Schwarz Edward M. Schwarz |
| author_facet | Yue Peng Yue Peng H. Mark Kenney H. Mark Kenney Karen L. de Mesy Bentley Karen L. de Mesy Bentley Lianping Xing Lianping Xing Christopher T. Ritchlin Christopher T. Ritchlin Edward M. Schwarz Edward M. Schwarz |
| author_sort | Yue Peng |
| collection | DOAJ |
| description | ObjectiveInflammatory-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.MethodsWhole mount immunofluorescent microscopy, toluidine blue stained histology, scanning electron microscopy, and in silico bioinformatics were performed to phenotype and quantify PLV mast cells. Ankle bone volumes were assessed by μCT, 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 KitW-sh/W-sh (cKit-/-), and TNF-tg x cKit-/- 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.ResultsPLVs are surrounded by MCT+/MCPT1+/MCPT4+ 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+/MCPT1-/MCPT4- mast cells were embedded within the PLV structure. In silico single-cell RNA-seq (scRNAseq) analyses identified a population of PLV-associated mast cells (marker genes: Mcpt4, Cma1, Cpa3, Tpsb2, Kit, Fcer1a & Gata2) with enhanced TGFβ-related signaling that are phenotypically distinct from known MC subsets in the Mouse Cell Atlas. cKit-/- mice have greater lymphatic defects than TNF-tg mice with exacerbation of lymphatic dysfunction and inflammatory-erosive arthritis in TNF-tg x cKit-/- vs. TNF-Tg mice. Cromolyn sodium therapy stabilized PLV mast cells, increased TNF-induced bone loss, synovitis, and osteoclasts, and decreased ICG clearance.ConclusionsMast 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. |
| first_indexed | 2024-03-08T23:28:51Z |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-08T23:28:51Z |
| publishDate | 2023-12-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-80288ec9980c44ea93b144bd10879db12023-12-14T16:41:20ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-12-011410.3389/fimmu.2023.12758711275871Distinct mast cell subpopulations within and around lymphatic vessels regulate lymph flow and progression of inflammatory-erosive arthritis in TNF-transgenic miceYue Peng0Yue Peng1H. Mark Kenney2H. Mark Kenney3Karen L. de Mesy Bentley4Karen L. de Mesy Bentley5Lianping Xing6Lianping Xing7Christopher T. Ritchlin8Christopher T. Ritchlin9Edward M. Schwarz10Edward M. Schwarz11Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, United StatesCenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, United StatesCenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, United StatesCenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, United StatesCenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Medicine, Division of Allergy, Immunology, Rheumatology, University of Rochester Medical Center, Rochester, NY, United StatesCenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, United StatesObjectiveInflammatory-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.MethodsWhole mount immunofluorescent microscopy, toluidine blue stained histology, scanning electron microscopy, and in silico bioinformatics were performed to phenotype and quantify PLV mast cells. Ankle bone volumes were assessed by μCT, 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 KitW-sh/W-sh (cKit-/-), and TNF-tg x cKit-/- 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.ResultsPLVs are surrounded by MCT+/MCPT1+/MCPT4+ 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+/MCPT1-/MCPT4- mast cells were embedded within the PLV structure. In silico single-cell RNA-seq (scRNAseq) analyses identified a population of PLV-associated mast cells (marker genes: Mcpt4, Cma1, Cpa3, Tpsb2, Kit, Fcer1a & Gata2) with enhanced TGFβ-related signaling that are phenotypically distinct from known MC subsets in the Mouse Cell Atlas. cKit-/- mice have greater lymphatic defects than TNF-tg mice with exacerbation of lymphatic dysfunction and inflammatory-erosive arthritis in TNF-tg x cKit-/- vs. TNF-Tg mice. Cromolyn sodium therapy stabilized PLV mast cells, increased TNF-induced bone loss, synovitis, and osteoclasts, and decreased ICG clearance.ConclusionsMast 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.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1275871/fullT32GM007356F30AG076326R01AG059775R01AR069000R01AR056702mast cell |
| spellingShingle | Yue Peng Yue Peng H. Mark Kenney H. Mark Kenney Karen L. de Mesy Bentley Karen L. de Mesy Bentley Lianping Xing Lianping Xing Christopher T. Ritchlin Christopher T. Ritchlin Edward M. Schwarz Edward M. Schwarz Distinct mast cell subpopulations within and around lymphatic vessels regulate lymph flow and progression of inflammatory-erosive arthritis in TNF-transgenic mice Frontiers in Immunology T32GM007356 F30AG076326 R01AG059775 R01AR069000 R01AR056702 mast cell |
| title | Distinct mast cell subpopulations within and around lymphatic vessels regulate lymph flow and progression of inflammatory-erosive arthritis in TNF-transgenic mice |
| title_full | Distinct mast cell subpopulations within and around lymphatic vessels regulate lymph flow and progression of inflammatory-erosive arthritis in TNF-transgenic mice |
| title_fullStr | Distinct mast cell subpopulations within and around lymphatic vessels regulate lymph flow and progression of inflammatory-erosive arthritis in TNF-transgenic mice |
| title_full_unstemmed | Distinct mast cell subpopulations within and around lymphatic vessels regulate lymph flow and progression of inflammatory-erosive arthritis in TNF-transgenic mice |
| title_short | Distinct mast cell subpopulations within and around lymphatic vessels regulate lymph flow and progression of inflammatory-erosive arthritis in TNF-transgenic mice |
| title_sort | distinct mast cell subpopulations within and around lymphatic vessels regulate lymph flow and progression of inflammatory erosive arthritis in tnf transgenic mice |
| topic | T32GM007356 F30AG076326 R01AG059775 R01AR069000 R01AR056702 mast cell |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1275871/full |
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