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，可以 归因于过度使用。靶向巨噬细胞及其分泌物治疗肌腱病的研究进展 促炎产品显示出希望，但收效甚微。流行的模型是Mac是一种 单细胞类型，对微环境中的提示做出反应，在亲-亲细胞之间可逆地转换 炎症(M1)和抗炎(M2)状态。相反，我们为mac提出了一个新的范例。 存在两种不同细胞类型的肌腱病：胚源性组织驻留MACs(EM)和成人 单核细胞来源的MACs(ADM)。近年来，免疫学领域已经背离了M1-M2模型 根据在肺、滑膜、脑、心脏和其他组织中发现的EM。EM在胚胎中发育， 局部存在于成人组织中，作为抗炎细胞，慢慢自我更新，并促进再生 受伤后。相比之下，ADM来源于骨髓来源的单核细胞，具有促炎作用。基于 这些令人兴奋的发现，我们假设在肌腱中EM是抗炎的，ADM是促炎的。 炎症，当ADM压倒肌腱中的EM时，就会发生肌腱病变。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，以及 由于ADM-to-EM的不同，女性和男性对肌腱病的易感性不同 平衡。由于ADM和EM的唯一标记尚不清楚，我们将通过使用 I)利用遗传小鼠模型对肌腱中的ADM和EM进行荧光标记的新命运映射策略 (基于它们的自我更新能力)，这将使ADM和EM的特征得以确定，以及ii)抑制 单核细胞的募集，从而操纵肌腱中的ADM数量。我们将诱发肌腱病 这些小鼠使用既定的下坡跑步机跑步方案，然后对ADM和EM进行特征分析 表型和功能与肌腱病严重程度的关系。我们预计成功的结果将成为 ADM和EM独特的标记图谱，并将显示ADM是促炎的，EM是抗炎的 炎症，较低的ADM-EM平衡(例如，细胞因子/趋化因子的比率)与较低的 不同跑时点肌腱病变的严重程度。结果还将确定假定的ADM-和EM- 在未来的研究中测试作为预防和治疗肌腱病的治疗剂的特定靶点。这项研究 将改变目前对肌腱病的理解，确定预防和治愈的新治疗靶点 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.