Telocyte Deletion is Associated with Loss of Lymphatic Drainage and Exacerbation of Inflammatory‐Erosive Arthritis in Mice

Objective Rheumatoid arthritis (RA) patients have lymphatic defects characterized by loss of collecting lymphatic vessel (cLV) contractions of unknown etiology. To elucidate underlying mechanisms, we generated transgenic mice with lymphatic‐specific inducible genetics and studied joint‐draining lymphatics in zymosan‐induced arthritis (ZIA). Methods We crossed novel Efhd1 ‐CreER T2 and Myoc ‐CreER T2 mice to Ai9 tdTtomato (tdT) reporter mice to assess tamoxifen‐induced transgene expression via scRNAseq, whole‐mount immunofluorescent microscopy (WMIFM), and immunohistochemistry (IHC). We applied electron and confocal microscopy of popliteal lymphatic vessels (PLVs) to examine αSMA + lymphatic muscle cells, MCT + mast cells, and CD31 ‐ /CD34 + cells. We crossed Efhd1 ‐CreER T2 and Myoc ‐CreER T2 mice to diphtheria toxin‐alpha floxed mice to examine: i) tamoxifen‐induced targeted cell deletion; ii) lymphatic function via near infrared imaging of injected indocyanine green; and iii) effects on ZIA in the knee via longitudinal ultrasound, micro‐CT, and histology. Results Multimodal microscopy discovered the presence of peri‐PLV spindle‐shaped cells with elongated cytoplasmic extensions physically integrated into mast cells. Gene expression studies confirmed these cells are consistent with telocytes, and WMIFM demonstrated peri‐PLV tdT + telocyte networks extending from capillaries in the ankle synovium to cLV near the knee. In vivo telocyte depletion decreased lymphatic drainage and exacerbated synovitis and focal erosions in ZIA. Conclusions Telocyte networks extend from the synovium into mast cells proximal to joint‐draining cLVs, and telocyte loss is associated with synovial lymphatic system (SLS) defects and exacerbated joint pathology from inflammatory‐erosive arthritis. Thus, SLS telocytes are a novel drug target for RA and interventions that maintain telocytes (e.g. exercise) may improve lymphatic function. image