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Summary: Lymphatic vessels are required for the clearance of excess fluid and immune cells from inflamed tissue, making the regulation of lymphangiogenesis an important area of research. Although the positive regulatory mechanisms of lymphangiogenesis are well known, the negative regulatory mechanisms observed during inflammation remain unclear. Here, we identify tenascin-C (TNC) as a spatiotemporal negative regulator of lymphangiogenesis during inflammation. We found an inverse correlation between lymphangiogenesis and TNC expression in a mouse lymphedema model. Genetic deletion of Tnc promotes lymphangiogenesis and improves lymphatic drainage function, thereby accelerating the resolution of inflammation. Conversely, the exogenous addition of TNC suppresses lymphangiogenesis and prolongs inflammation. TNC inhibits the proliferation and promotes apoptosis of lymphatic endothelial cells. Mechanistically, TNC facilitates integrin αvβ1 heterodimer formation, leading to the activation of non-canonical (TAK1/p38MAPK/ATF-2) TGFβ signaling to suppress lymphangiogenesis. Our study highlights the importance of negative regulation of lymphangiogenesis in modulating immune responses.

Summary: Primary cilia play a pivotal role in signal transduction and development and are known to serve as signaling hubs. Recent studies have shown that primary cilium dysfunction influences adipogenesis, but the mechanisms are unclear. Here, we show that mesenchymal progenitors C3H10T1/2 depleted of trichoplein, a key regulator of cilium formation, have significantly longer cilia than control cells and fail to differentiate into adipocytes. Mechanistically, the elongated cilia prevent caveolin-1- and/or GM3-positive lipid rafts from being assembled around the ciliary base where insulin receptor proteins accumulate, thereby inhibiting the insulin-Akt signaling. We further generate trichoplein knockout mice, in which adipogenic progenitors display elongated cilia and impair the lipid raft dynamics. The knockout mice on an extended high-fat diet exhibit reduced body fat and smaller adipocytes than wild-type (WT) mice. Overall, our results suggest a role for primary cilia in regulating adipogenic signal transduction via control of the lipid raft dynamics around cilia.