Vitamin D improves sunburns by increasing autophagy in M2 macrophages

Lopa M. Das, Amy M. Binko, Zachary P. Traylor, Han Peng, Kurt Q. Lu*

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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. Abbreviations: ARG1: arginase 1; ATG7 cKO: autophagy related 7 conditional knockout; HPF: high powered field; KLF4: Kruppel like factor 4; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; macs: macrophage; 3-MA: 3-methyladenine; MMP9: matrix metallopeptidase 9; NOS2: nitric oxide synthase 2, inducible; PPARG: peroxisome proliferator activated receptor gamma; SQSTM1/p62: sequestosome 1; TNF: tumor necrosis factor; UV: ultraviolet; VD: vitamin D, 25-hydroxy vitamin D 3 ; 1,25-VD: 1, 25-dihydroxy vitamin D 3 .

Original languageEnglish (US)
Pages (from-to)813-826
Number of pages14
JournalAutophagy
Volume15
Issue number5
DOIs
StatePublished - May 4 2019

Fingerprint

Sunburn
Autophagy
Vitamin D
Macrophages
Skin
Inflammation
Cholecalciferol
Wounds and Injuries
Anti-Inflammatory Agents
Arginase
Microtubule-Associated Proteins
PPAR gamma
Metalloproteases
Nitric Oxide Synthase Type II
Myeloid Cells
Regeneration
Electron Microscopy
Down-Regulation
Tumor Necrosis Factor-alpha

Keywords

  • Autophagy
  • UV
  • inflammation
  • macrophage
  • vitamin D

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Das, Lopa M. ; Binko, Amy M. ; Traylor, Zachary P. ; Peng, Han ; Lu, Kurt Q. / Vitamin D improves sunburns by increasing autophagy in M2 macrophages. In: Autophagy. 2019 ; Vol. 15, No. 5. pp. 813-826.
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abstract = "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. Abbreviations: ARG1: arginase 1; ATG7 cKO: autophagy related 7 conditional knockout; HPF: high powered field; KLF4: Kruppel like factor 4; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; macs: macrophage; 3-MA: 3-methyladenine; MMP9: matrix metallopeptidase 9; NOS2: nitric oxide synthase 2, inducible; PPARG: peroxisome proliferator activated receptor gamma; SQSTM1/p62: sequestosome 1; TNF: tumor necrosis factor; UV: ultraviolet; VD: vitamin D, 25-hydroxy vitamin D 3 ; 1,25-VD: 1, 25-dihydroxy vitamin D 3 .",
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Vitamin D improves sunburns by increasing autophagy in M2 macrophages. / Das, Lopa M.; Binko, Amy M.; Traylor, Zachary P.; Peng, Han; Lu, Kurt Q.

In: Autophagy, Vol. 15, No. 5, 04.05.2019, p. 813-826.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Vitamin D improves sunburns by increasing autophagy in M2 macrophages

AU - Das, Lopa M.

AU - Binko, Amy M.

AU - Traylor, Zachary P.

AU - Peng, Han

AU - Lu, Kurt Q.

PY - 2019/5/4

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N2 - 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. Abbreviations: ARG1: arginase 1; ATG7 cKO: autophagy related 7 conditional knockout; HPF: high powered field; KLF4: Kruppel like factor 4; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; macs: macrophage; 3-MA: 3-methyladenine; MMP9: matrix metallopeptidase 9; NOS2: nitric oxide synthase 2, inducible; PPARG: peroxisome proliferator activated receptor gamma; SQSTM1/p62: sequestosome 1; TNF: tumor necrosis factor; UV: ultraviolet; VD: vitamin D, 25-hydroxy vitamin D 3 ; 1,25-VD: 1, 25-dihydroxy vitamin D 3 .

AB - 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. Abbreviations: ARG1: arginase 1; ATG7 cKO: autophagy related 7 conditional knockout; HPF: high powered field; KLF4: Kruppel like factor 4; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; macs: macrophage; 3-MA: 3-methyladenine; MMP9: matrix metallopeptidase 9; NOS2: nitric oxide synthase 2, inducible; PPARG: peroxisome proliferator activated receptor gamma; SQSTM1/p62: sequestosome 1; TNF: tumor necrosis factor; UV: ultraviolet; VD: vitamin D, 25-hydroxy vitamin D 3 ; 1,25-VD: 1, 25-dihydroxy vitamin D 3 .

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