Vitamin D improves sunburns by increasing autophagy in M2 macrophages
Vitamin D improves sunburns by increasing autophagy in M2 macrophages
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DOI：
10.1080/15548627.2019.1569298
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发表时间：
2019-05-04
期刊：
影响因子：
13.3
通讯作者：
Lu, Kurt Q.
中科院分区：
文献类型：
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作者：
Das, Lopa M.;Binko, Amy M.;Lu, Kurt Q.
暴露在紫外线辐射下的皮肤炎症会导致表皮损伤、细胞渗透和促炎介质的分泌，从而加剧组织破坏。恢复主要是由抗炎的M2巨噬细胞介导的，它抑制炎症并促进表皮再生。维生素D能够抗炎，促进组织对损伤的修复。由于维生素D增强了细胞的巨自噬/自噬，我们研究了自噬在维生素D保护紫外线介导的晒伤和炎症中的作用。使用紫外线介导的急性皮肤损伤小鼠模型，我们证明了单剂量维生素D通过持续抑制与髓系抗炎M2巨噬细胞自噬增强相关的炎症细胞因子来解决损伤。MAP1LC3B/LC3的表达增加证实了电子显微镜检测到的完全自溶酶体的形成，并与维生素D治疗后皮肤中SQSTM1/p62的降解有关。具体地说，抑制自噬的药物增加了紫外线诱导的细胞凋亡，抑制了M2 MACs的募集，并阻止了维生素D下调皮肤中的肿瘤坏死因子和MMP9。此外，ATG7 CKO小鼠髓系细胞中自噬的选择性删除取消了维生素D介导的保护，并重现了紫外线诱导的炎症。从机制上讲，维生素D信号激活了M2自噬调节因子Klf4、PPARG和Arg1。最后，对暴露在紫外线下的人类皮肤活检组织的分析发现，在维生素D干预后，巨噬细胞自噬功能也有类似的增加，确定了自噬在维生素D介导的皮肤保护中的关键作用。
Cutaneous inflammation from UV radiation exposure causes epidermal damage, cellular infiltration, and secretion of pro-inflammatory mediators that exacerbate tissue destruction. Recovery is mediated chiefly by anti-inflammatory M2 macrophages that suppress inflammation and augment epidermal regeneration. Vitamin D enables anti-inflammation to promote tissue repair in response to injury. Since vitamin D enhances cellular macroautophagy/autophagy, we investigated the role of autophagy in vitamin D protection of UV-mediated sunburn and inflammation. Using a UV-mediated acute skin injury mouse model, we demonstrate that a single dose of vitamin D resolves injury with sustained inhibition of inflammatory cytokines associated with enhanced autophagy in myeloid anti-inflammatory M2 macs. Increased MAP1LC3B/LC3 expression corroborated with complete autolysosome formation detected by electron microscopy and correlated with degradation of SQSTM1/p62 in the skin following vitamin D treatment. Specifically, pharmacological inhibition of autophagy increased UV-induced apoptosis, suppressed M2 macs recruitment, and prevented vitamin D downregulation of Tnf and Mmp9 in the skin. Furthermore, selective deletion of autophagy in myeloid cells of atg7 cKO mice abrogated vitamin D-mediated protection and recapitulated UV-induced inflammation. Mechanistically, vitamin D signaling activated M2-autophagy regulators Klf4, Pparg, and Arg1. Lastly, analysis of UV-exposed human skin biopsies detected a similar increase in macrophage autophagy following vitamin D intervention, identifying an essential role for autophagy in vitamin D-mediated protection of skin from UV damage.