CSF1R-dependent macrophages in the salivary gland are essential for epithelial regeneration following radiation-induced injury
CSF1R-dependent macrophages in the salivary gland are essential for epithelial regeneration following radiation-induced injury
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DOI：
10.1101/2022.06.12.495803
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发表时间：
2022-06
期刊：
影响因子：
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通讯作者：
J. McKENDRICK;G. Jones;Sonia S. Elder;Ella Mercer;M. Magalhaes;C. Rocchi;L. Hegarty;A. L. Johnson-A
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文献类型：
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作者：
J. McKENDRICK;G. Jones;Sonia S. Elder;Ella Mercer;M. Magalhaes;C. Rocchi;L. Hegarty;A. L. Johnson-A
在接受头颈部癌症放射治疗的个体中，唾液腺经常受损，导致口干症或慢性口干。这导致对他们的健康和生活质量的有害影响，对此没有再生疗法。巨噬细胞是唾液腺中的主要细胞类型，并且由于其无与伦比的驱动组织修复和再生的能力而成为有吸引力的治疗靶点。然而，巨噬细胞在唾液腺稳态中的性质和作用以及它们是否有助于损伤后的组织修复/再生还没有很好地理解。在这里，我们使用单细胞RNA-seq，多参数流式细胞术和荧光显微镜来绘制整个发育过程中和辐射诱导损伤后唾液腺巨噬细胞区室的异质性。我们发现，有高度动态变化的唾液腺巨噬细胞隔室的组成与年龄，部分原因是由于这些细胞的个体发育的变化，确定使用一套互补的命运映射系统。突变小鼠和抗体阻断的组合表明，唾液腺巨噬细胞的发育和维持依赖于CSF 1，而不是IL-34或GM-CSF。最后，使用一个体内模型的辐射诱导的唾液腺损伤结合一种新的Mafb特异性耗竭系统，我们证明了巨噬细胞的重要作用。没有巨噬细胞，具有DNA损伤的细胞的清除以及这种损伤后的有效组织修复严重受阻。因此，我们的数据表明，一个强有力的情况下，探索操纵巨噬细胞的治疗潜力，以促进组织修复，从而尽量减少放射治疗后的唾液腺功能障碍。
The salivary glands often become damaged in individuals receiving radiotherapy for head and neck cancer, resulting in xerostomia, or chronic dry mouth. This leads to detrimental effects on their health and quality of life, for which there is no regenerative therapy. Macrophages are the predominant cell type in the salivary glands and are attractive therapeutic targets due to their unrivalled capacity to drive tissue repair and regeneration. Yet, the nature and role of macrophages in salivary gland homeostasis and whether or not they contribute to tissue repair/regeneration following injury is not well understood. Here, we have used single cell RNA-seq, multi-parameter flow cytometry and fluorescence microscopy to map the heterogeneity of the salivary gland macrophage compartment throughout development and following radiation-induced injury. We show that there are highly dynamic changes in the composition of the salivary gland macrophage compartment with age, in part due to changes in the ontogeny of these cells, determined using a suite of complementary fate mapping systems. A combination of mutant mice and antibody blockade demonstrates that salivary gland macrophages are dependent on CSF1, but not IL-34 or GM-CSF, for their development and maintenance. Finally, using an in vivo model of radiation-induced salivary gland injury combined with a novel Mafb-specific depletion system, we demonstrate an essential role for macrophages. Without macrophages the clearance of cells with DNA damage, and effective tissue repair following such injury, is severely comprised. Our data, therefore, indicate a strong case for exploring the therapeutic potential of manipulating macrophages in order to promote tissue repair and thus minimise salivary gland dysfunction after radiotherapy.