Role of distinct fibroblast lineages and immune cells in dermal repair following UV radiation-induced tissue damage.
Role of distinct fibroblast lineages and immune cells in dermal repair following UV radiation-induced tissue damage.
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DOI：
10.7554/elife.71052
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发表时间：
2021-12-23
期刊：
影响因子：
7.7
通讯作者：
Watt FM
中科院分区：
文献类型：
--
作者：
Rognoni E;Goss G;Hiratsuka T;Sipilä KH;Kirk T;Kober KI;Lui PP;Tsang VS;Hawkshaw NJ;Pilkington SM;Cho I;Ali N;Rhodes LE;Watt FM
太阳紫外线辐射(UVR)是皮肤损伤的主要来源，导致炎症、过早衰老和癌症。虽然UVR诱导的几种改变，包括细胞外基质重组和表皮DNA损伤，已经被记录在案，但不同的成纤维细胞系的作用及其与免疫细胞的联系尚未被探索。我们发现，急性和慢性紫外线照射会导致人和小鼠皮肤上真皮成纤维细胞的选择性丢失。血统追踪和活体成像显示，急性UVR后的修复主要由乳头状成纤维细胞增殖和成纤维细胞重组进行，迁移最少。相比之下，慢性UVR暴露会导致乳头状成纤维细胞的永久性丧失，成纤维细胞膜突起的扩张部分补偿了细胞数量的减少。虽然紫外线照射强烈地激活了皮肤中的Wnt信号，但通过稳定表皮β-catenin来刺激成纤维细胞的增殖并不能促进乳头状真皮的修复。急性UVR导致中性粒细胞和T细胞亚群的渗入，并增加了皮肤中促炎症的前列腺素信号。CD4和CD8阳性细胞的耗尽导致乳头状成纤维细胞耗竭增加，这与DNA损伤、促炎前列腺素增加和成纤维细胞增殖减少有关。相反，局部应用COX-2抑制可防止UVR后成纤维细胞的耗竭和中性粒细胞的浸润。我们得出结论，乳头状成纤维细胞的丢失主要是由一种非调节性的炎症反应引起的，在UVR诱导的环境应激下，浸润性T细胞支持成纤维细胞的存活。
Solar ultraviolet radiation (UVR) is a major source of skin damage, resulting in inflammation, premature ageing, and cancer. While several UVR-induced changes, including extracellular matrix reorganisation and epidermal DNA damage, have been documented, the role of different fibroblast lineages and their communication with immune cells has not been explored. We show that acute and chronic UVR exposure led to selective loss of fibroblasts from the upper dermis in human and mouse skin. Lineage tracing and in vivo live imaging revealed that repair following acute UVR is predominantly mediated by papillary fibroblast proliferation and fibroblast reorganisation occurs with minimal migration. In contrast, chronic UVR exposure led to a permanent loss of papillary fibroblasts, with expansion of fibroblast membrane protrusions partially compensating for the reduction in cell number. Although UVR strongly activated Wnt signalling in skin, stimulation of fibroblast proliferation by epidermal β-catenin stabilisation did not enhance papillary dermis repair. Acute UVR triggered an infiltrate of neutrophils and T cell subpopulations and increased pro-inflammatory prostaglandin signalling in skin. Depletion of CD4- and CD8-positive cells resulted in increased papillary fibroblast depletion, which correlated with an increase in DNA damage, pro-inflammatory prostaglandins, and reduction in fibroblast proliferation. Conversely, topical COX-2 inhibition prevented fibroblast depletion and neutrophil infiltration after UVR. We conclude that loss of papillary fibroblasts is primarily induced by a deregulated inflammatory response, with infiltrating T cells supporting fibroblast survival upon UVR-induced environmental stress.