Macrophage-derived Wnt signaling increases endothelial permeability during skeletal muscle injury
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Inflammation Research
ORIGINAL RESEARCH PAPER
Macrophage‑derived Wnt signaling increases endothelial permeability during skeletal muscle injury S. Tusavitz1 · S. Keoonela1 · M. Kalkstein1 · S. McCormick1 · B. Gasser1 · M. Arrigale1 · P. Rafferty1 · A. C. Carpenter1 Received: 28 June 2020 / Revised: 4 August 2020 / Accepted: 23 August 2020 © Springer Nature Switzerland AG 2020
Abstract Objective The inflammatory response and the presence of macrophages are reported to be necessary for proper muscle regeneration. However, our understanding of the molecular mechanisms governing how macrophages signal to promote muscle regeneration is incomplete. Methods and results Here we conditionally deleted Wls, which is required for Wnt secretion, from macrophages and examined the impact on endothelial permeability following muscle injury. The expression of Wnt ligands and Wls was increased in the tibialis anterior (TA) of mice 2 days following B aCl2 injury. Loss of macrophage Wls inhibited the loss of endothelial barrier function, as measured by transendothelial resistance and Evans blue dye permeability assays. Interestingly, the blockade in endothelial permeability correlated with reduced VEGF levels and pretreatment of wild type endothelial cells with a VEGFR2 blocking antibody was sufficient to reduce endothelial permeability induced by stimulated macrophage supernatant. We also found that macrophage Wls-null TAs had myocytes with reduced cross-sectional area 7 day post-injury suggesting a delay in muscle regeneration. Conclusion Our results indicate that macrophage-derived Wnt signaling increases endothelial permeability in a VEGFdependent fashion following muscle injury. Our findings implicate macrophages as a primary source of Wnt ligands following muscle injury and highlight the Wnt pathway as a therapeutic target following injury. Keywords Macrophage · Wnt · Endothelial · Permeability · Skeletal muscle
Introduction Permeability of the microvasculature is controlled by the state of organization of the endothelial junctional complexes that limit large plasma macromolecules and cells entry into tissue from the blood stream. Permeability is often studied as a characteristic of pathologies, but is also important during the early stages of injury for wound healing and resolution [1]. Opening of endothelial junctions increases protein leakage elevating interstitial fluid that will be flushed through the immune surveilling lymphatic system. Leaked fibrinogen forms a temporary matrix closing wounds and serves as a possible platform for the assembly of new blood vessels [2]. Responsible Editor: John Di Battista. * A. C. Carpenter [email protected] 1
Health and Exercise Physiology, Ursinus College, 601 E. Main St, Collegeville, PA 19426, USA
Finally, open endothelial junctions are a preferred route for blood leukocytes, primarily activated neutrophils and monocytes, to enter damaged tissue [3]. Macrophages are required for efficient skeletal muscle healing [4, 5]. Indeed, macrophage depletion prior to muscle
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