Wednesday, December 4, 2024
12/4/2024
Abstract. Tendinopathy is associated with chronic fibrosis and altered mechanical properties and can be attributed to overuse. Approaches to treat tendinopathy by targeting macrophages (macs) and their secreted pro-inflammatory products show promise but with limited success. The prevailing model is that macs are a single cell type that responds to cues in the microenvironment to transition reversibly between pro- inflammatory (M1) and anti-inflammatory (M2) states. In contrast, we propose a new paradigm for macs in tendinopathy in which two distinct cell types exist: embryo-derived tissue resident macs (EM) and adult monocyte-derived macs (AdM). In recent years, the immunology field has departed from the M1-M2 model based on discoveries of EM in lung, synovium, brain, heart, and other tissues. EM develop in the embryo, locally persist in adult tissues as anti-inflammatory cells, are slowly self-renewing, and promote regeneration after injury. In contrast, AdM derive from bone marrow-derived monocytes and are pro-inflammatory. Based on these exciting findings, we hypothesize that in tendons EM are anti-inflammatory and AdM are pro- inflammatory, and that tendinopathy develops when AdM overwhelm EM in the tendon. We also hypothesize that altering AdM-to-EM balance (e.g., ratios of cytokines/chemokines) can prevent and heal tendinopathy, and that females and males exhibit different susceptibilities to tendinopathy due to differences in AdM-to-EM balance. Because unique markers for AdM and EM are yet unknown, we will test these hypotheses by utilizing i) novel fate-mapping strategies with genetic mouse models to fluorescently label AdM and EM in tendons (based on their self-renewing capabilities) which will enable characterization of AdM and EM, and ii) inhibition of monocyte recruitment to thereby manipulate AdM numbers in the tendon. We will induce tendinopathy in these mice using an established downhill treadmill running protocol and then characterize AdM and EM phenotypes and functions relative to severity of tendinopathy. We expect successful outcomes will characterize unique marker profiles of AdM and EM, and will show that AdM are pro-inflammatory, that EM are anti- inflammatory, and that lower AdM-to-EM balance (e.g. ratios of cytokines/chemokines) correlates with lower severity of tendinopathy at different timepoints of running. Outcomes will also identify putative AdM- and EM- specific targets to test in future studies as therapeutic agents to prevent and heal tendinopathy. This research will transform current understanding of tendinopathy, identify novel therapeutic targets to prevent and heal tendinopathy, and pioneer a new field of tendon macrophage biology.
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