CSF1R-dependent macrophages in the salivary gland are essential for epithelial regeneration after radiation-induced injury
CSF1R-dependent macrophages in the salivary gland are essential for epithelial regeneration after radiation-induced injury
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DOI：
10.1126/sciimmunol.add4374
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发表时间：
2023-11
影响因子：
24.8
通讯作者：
John G. McKendrick;Gareth-Rhys Jones;Sonia S. Elder;Erin Watson;W. T’Jonck;Ella Mercer;Marlene S. Maga
中科院分区：
文献类型：
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作者：
John G. McKendrick;Gareth-Rhys Jones;Sonia S. Elder;Erin Watson;W. T’Jonck;Ella Mercer;Marlene S. Maga
在接受头颈癌放疗的患者中，唾液腺经常受损，导致慢性口干。这对他们的健康和生活质量造成了不利影响，对此没有再生疗法。巨噬细胞是唾液腺中的主要免疫细胞，由于其无与伦比的驱动组织修复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如何促进损伤后的组织修复尚不清楚。在这里，我们发现至少有两个表型和转录不同的CX3CR1+巨噬细胞群体存在于成人唾液腺中，它们占据解剖学上不同的生态位。CD11c+CD206 - CD163 -巨噬细胞通常与腺体上皮相关，而CD11c - CD206+CD163+巨噬细胞通常与血管和神经相关。使用一套互补的命运映射系统，我们表明唾液腺巨噬细胞的个体发生和组成随着年龄的增长而发生高度动态的变化。利用辐射诱导的唾液腺损伤结合遗传或抗体介导的巨噬细胞耗竭的体内模型，我们证明了巨噬细胞在清除DNA损伤细胞中的重要作用。此外，我们发现上皮相关巨噬细胞对于辐射损伤后有效的组织修复和腺体功能是必不可少的，它们的消耗导致唾液分泌减少。因此，我们的数据为探索操纵巨噬细胞促进组织修复的治疗潜力提供了强有力的案例，从而最大限度地减少放射治疗后唾液腺功能障碍。长寿命的巨噬细胞是放射治疗损伤后颌下腺再生所必需的。放射治疗是头颈癌的有效治疗方法，但伴随而来的是一系列的副作用，包括慢性口干。McKendrick等人研究了巨噬细胞在唾液腺中的作用，以更好地了解它们对辐射的反应以及如何靶向它们以恢复功能。他们在成年小鼠的唾液腺中发现了两个转录不同的CX3CR1+巨噬细胞亚群。腺上皮富集CD11c+ CD206-CD163 -巨噬细胞，而CD11c - cd206 +CD163+巨噬细胞定位于血管和神经。辐射诱导的唾液腺损伤小鼠模型证实，这种治疗改变了该部位巨噬细胞亚群的组成和寿命，但上皮相关的CD11c+ CD206-CD163 -巨噬细胞在损伤后特异性地需要上皮细胞再生。这些发现为唾液腺对辐射的反应提供了见解，并可以指导未来的治疗。克里斯蒂安娜福格
The salivary glands often become damaged in individuals receiving radiotherapy for head and neck cancer, resulting in 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 immune cell in the salivary glands and are attractive therapeutic targets due to their unrivaled capacity to drive tissue repair. Yet, the nature and role of macrophages in salivary gland homeostasis and how they may contribute to tissue repair after injury are not well understood. Here, we show that at least two phenotypically and transcriptionally distinct CX3CR1+ macrophage populations are present in the adult salivary gland, which occupy anatomically distinct niches. CD11c+CD206–CD163– macrophages typically associate with gland epithelium, whereas CD11c−CD206+CD163+ macrophages associate with blood vessels and nerves. Using a suite of complementary fate mapping systems, we show that there are highly dynamic changes in the ontogeny and composition of salivary gland macrophages with age. Using an in vivo model of radiation-induced salivary gland injury combined with genetic or antibody-mediated depletion of macrophages, we demonstrate an essential role for macrophages in clearance of cells with DNA damage. Furthermore, we show that epithelial-associated macrophages are indispensable for effective tissue repair and gland function after radiation-induced injury, with their depletion resulting in reduced saliva production. Our data, therefore, provide a strong case for exploring the therapeutic potential of manipulating macrophages to promote tissue repair and thus minimize salivary gland dysfunction after radiotherapy. Description Long-lived macrophages in the submandibular salivary gland are necessary for regeneration after radiotherapy injury. Editor’s summary Radiation therapy is an effective treatment for head and neck cancer but comes with a wide range of side effects, including chronic dry mouth. McKendrick et al. investigated the role of macrophages in salivary glands to better understand their response to radiation and how they can be targeted to restore function. They identified two transcriptionally distinct CX3CR1+ macrophage subsets in salivary glands of adult mice. The gland epithelium was enriched for CD11c+CD206–CD163– macrophages, whereas CD11c–CD206+CD163+ macrophages localized to blood vessels and nerves. A mouse model of radiation-induced salivary gland injury confirmed that this treatment changes the composition and longevity of macrophage subsets at this site, but epithelium-associated CD11c+CD206–CD163– macrophages specifically are required for epithelial cell regeneration after injury. These findings provide insights into salivary gland responses to irradiation and can guide future therapies. —Christiana Fogg