Tissue Resident Macrophage Effects on Tendon Health

抽象的。肌腱病与慢性纤维化和机械性能改变有关， 归因于过度使用。通过靶向巨噬细胞（macs）及其分泌物治疗肌腱病的方法 促炎产品显示出前景，但成功有限。流行的模式是，Mac电脑是一个 单细胞类型，响应微环境中的提示，在亲- 炎症（M1）和抗炎（M2）状态。相比之下，我们提出了一个新的范例， 存在两种不同细胞类型的肌腱病：胚胎来源的组织驻留细胞（EM）和成人 单核细胞衍生的MAC（AdM）。近年来，免疫学领域已经脱离了M1-M2模型 基于在肺、滑膜、脑、心脏和其他组织中发现EM。EM在胚胎中发育， 作为抗炎细胞局部存在于成人组织中，缓慢自我更新并促进再生 伤后相反，AdM来源于骨髓来源的单核细胞，并且是促炎性的。基于 这些令人兴奋的发现，我们假设，在肌腱EM是抗炎和AdM是亲， 当AdM在肌腱中压倒EM时，肌腱病变发展。我们还假设 改变ADM与EM的平衡（例如，细胞因子/趋化因子的比率）可以预防和治愈肌腱病，并且 由于AdM与EM的差异，女性和男性对肌腱病变表现出不同的易感性， 平衡由于AdM和EM的独特标记物尚不清楚，我们将通过使用 i）用遗传小鼠模型荧光标记肌腱中的AdM和EM的新的命运作图策略 （基于它们的自我更新能力），这将使得能够表征AdM和EM，以及ii）抑制 单核细胞的募集，从而操纵肌腱中的AdM数量。我们会在你的膝盖上 这些小鼠使用已建立的下坡跑步机跑步方案，然后表征AdM和EM 与肌腱病严重程度相关的表型和功能。我们预计，成功的结果将体现 AdM和EM的独特标志物谱，并将显示AdM是促炎性的，EM是抗炎性的， 炎性，并且较低的AdM-与-EM平衡（例如细胞因子/趋化因子的比率）与较低的AdM-与-EM平衡（例如细胞因子/趋化因子的比率）相关。 跑步不同时间点肌腱病的严重程度。结果还将确定推定的AdM-和EM- 在未来的研究中测试特定的靶点，作为预防和治愈肌腱病的治疗剂。本研究 将改变目前对肌腱病的理解，确定新的治疗靶点，以预防和治愈 肌腱病，并开创了肌腱巨噬细胞生物学的新领域。

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.