Chronic infection stunts macrophage heterogeneity and disrupts immune-mediated myogenesis
Chronic infection stunts macrophage heterogeneity and disrupts immune-mediated myogenesis
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DOI：
10.1172/jci.insight.121549
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发表时间：
2018-09-20
期刊：
影响因子：
8
通讯作者：
Wohlfert, Elizabeth A.
中科院分区：
文献类型：
--
作者：
Jin, Richard M.;Warunek, Jordan;Wohlfert, Elizabeth A.
骨骼肌强大的再生潜力对于在包括运动、感染和创伤在内的许多潜在损伤中维持组织功能至关重要。多个免疫群体，特别是巨噬细胞的高度协调作用，在指导这种修复程序中起着不可或缺的作用。然而，目前尚不清楚骨骼肌修复如何在慢性炎症环境中进行，例如感染，其中已经参与了主动免疫反应。为了解决这个问题，我们使用心脏毒素损伤模型来挑战慢性感染肌肉的修复潜力。与再生的幼稚骨骼肌相比，感染的骨骼肌表现出延迟肌肉修复的多个指标，包括对损伤的不同形态反应和生肌调节因子的表达失调。此外，使用流式细胞术和单细胞RNA测序方法，我们表明，减少巨噬细胞异质性，由于延迟出现的恢复性子集的基础功能障碍的组织修复在慢性感染。我们的研究结果强调了组织内预先存在的炎症环境如何改变修复性免疫，并最终改变组织再生的质量。
The robust regenerative potential of skeletal muscle is imperative for the maintenance of tissue function across a host of potential insults including exercise, infection, and trauma. The highly coordinated action of multiple immune populations, especially macrophages, plays an indispensable role in guiding this reparative program. However, it remains unclear how skeletal muscle repair proceeds in a chronically inflamed setting, such as infection, where an active immune response is already engaged. To address this question, we used a cardiotoxin injury model to challenge the reparative potential of chronically infected muscle. Compared with regenerating naive skeletal muscle, infected skeletal muscle exhibited multiple indicators of delayed muscle repair including a divergent morphologic response to injury and dysregulated expression of myogenic regulatory factors. Further, using both flow cytometric and single-cell RNA sequencing approaches, we show that reduced macrophage heterogeneity due to delayed emergence of restorative subsets underlies dysfunctional tissue repair during chronic infection. Our findings highlight how the preexisting inflammatory environment within tissue alters reparative immunity and ultimately the quality of tissue regeneration.