Vitamin D3 ameliorates nitrogen mustard‐induced cutaneous inflammation by inactivating the NLRP3 inflammasome through the SIRT3–SOD2–mtROS signaling pathway
Abstract Nitrogen mustard (NM) causes severe skin injury with an obvious inflammatory response, which is lack of effective and targeted therapies. Vitamin D3 (VD3) has excellent anti‐inflammatory properties and is considered as a potential candidate for the treatment of NM‐induced dermal toxicity; h...
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| Format: | Article |
| Language: | English |
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Wiley
2021-02-01
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| Series: | Clinical and Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ctm2.312 |
| _version_ | 1797894303088902144 |
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| author | Xunhu Dong Ying He Feng Ye Yuanpeng Zhao Jin Cheng Jingsong Xiao Wenpei Yu Jiqing Zhao Yan Sai Guorong Dan Mingliang Chen Zhongmin Zou |
| author_facet | Xunhu Dong Ying He Feng Ye Yuanpeng Zhao Jin Cheng Jingsong Xiao Wenpei Yu Jiqing Zhao Yan Sai Guorong Dan Mingliang Chen Zhongmin Zou |
| author_sort | Xunhu Dong |
| collection | DOAJ |
| description | Abstract Nitrogen mustard (NM) causes severe skin injury with an obvious inflammatory response, which is lack of effective and targeted therapies. Vitamin D3 (VD3) has excellent anti‐inflammatory properties and is considered as a potential candidate for the treatment of NM‐induced dermal toxicity; however, the underlying mechanisms are currently unclear. Cyclooxygenase‐2 (COX2; a widely used marker of skin inflammation) plays a key role in NM‐induced cutaneous inflammation. Herein, we initially confirmed that NM markedly promoted COX2 expression in vitro and in vivo. NM also increased NOD‐like receptor family pyrin domain containing 3 (NLRP3) expression, caspase‐1 activity, and interleukin‐1β (IL‐1β) release. Notably, treatment with a caspase‐1 inhibitor (zYVAD‐fmk), NLRP3 inhibitor (MCC950), and NLRP3 or caspase‐1 siRNA attenuated NM‐induced NLRP3 inflammasome activation, with subsequent suppression of COX2 expression and IL‐1β release in keratinocytes. Meanwhile, NM increased mitochondrial reactive oxygen species (mtROS) and decreased manganese superoxide dismutase 2 (SOD2) and sirtuin 3 (SIRT3) activities. Mito‐TEMPO (a mtROS scavenger) ameliorated NM‐caused NLRP3 inflammasome activation in keratinocytes. Moreover, VD3 improved SIRT3 and SOD2 activities, decreased mtROS contents, inactivated the NLRP3 inflammasome, and attenuated cutaneous inflammation induced by NM in vitro and in vivo. The beneficial activity of VD3 against NM‐triggered cutaneous inflammation was enhanced by the inhibitors of IL‐1, mtROS, NLRP3, caspase‐1, and NLRP3 or caspase‐1 siRNAs, which was abolished in SIRT3 inhibitor or SIRT3 siRNA‐treated keratinocytes and skins from SIRT3−/− mice. In conclusion, VD3 ameliorated NM‐induced cutaneous inflammation by inactivating the NLRP3 inflammasome, which was partially mediated through the SIRT3–SOD2–mtROS signaling pathway. |
| first_indexed | 2024-04-10T07:07:55Z |
| format | Article |
| id | doaj.art-0063ab019add40b5824d9a1048a89380 |
| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-04-10T07:07:55Z |
| publishDate | 2021-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj.art-0063ab019add40b5824d9a1048a893802023-02-27T05:10:47ZengWileyClinical and Translational Medicine2001-13262021-02-01112n/an/a10.1002/ctm2.312Vitamin D3 ameliorates nitrogen mustard‐induced cutaneous inflammation by inactivating the NLRP3 inflammasome through the SIRT3–SOD2–mtROS signaling pathwayXunhu Dong0Ying He1Feng Ye2Yuanpeng Zhao3Jin Cheng4Jingsong Xiao5Wenpei Yu6Jiqing Zhao7Yan Sai8Guorong Dan9Mingliang Chen10Zhongmin Zou11Department of Chemical Defense Medicine, School of Military Preventive Medicine Third Military Medical University (Army Medical University) Chongqing ChinaDepartment of Ultrasound Xinqiao Hospital Third Military Medical University (Army Medical University) Chongqing ChinaDepartment of Chemical Defense Medicine, School of Military Preventive Medicine Third Military Medical University (Army Medical University) Chongqing ChinaDepartment of Chemical Defense Medicine, School of Military Preventive Medicine Third Military Medical University (Army Medical University) Chongqing ChinaDepartment of Chemical Defense Medicine, School of Military Preventive Medicine Third Military Medical University (Army Medical University) Chongqing ChinaDepartment of Chemical Defense Medicine, School of Military Preventive Medicine Third Military Medical University (Army Medical University) Chongqing ChinaDepartment of Chemical Defense Medicine, School of Military Preventive Medicine Third Military Medical University (Army Medical University) Chongqing ChinaDepartment of Chemical Defense Medicine, School of Military Preventive Medicine Third Military Medical University (Army Medical University) Chongqing ChinaDepartment of Chemical Defense Medicine, School of Military Preventive Medicine Third Military Medical University (Army Medical University) Chongqing ChinaDepartment of Chemical Defense Medicine, School of Military Preventive Medicine Third Military Medical University (Army Medical University) Chongqing ChinaDepartment of Chemical Defense Medicine, School of Military Preventive Medicine Third Military Medical University (Army Medical University) Chongqing ChinaDepartment of Chemical Defense Medicine, School of Military Preventive Medicine Third Military Medical University (Army Medical University) Chongqing ChinaAbstract Nitrogen mustard (NM) causes severe skin injury with an obvious inflammatory response, which is lack of effective and targeted therapies. Vitamin D3 (VD3) has excellent anti‐inflammatory properties and is considered as a potential candidate for the treatment of NM‐induced dermal toxicity; however, the underlying mechanisms are currently unclear. Cyclooxygenase‐2 (COX2; a widely used marker of skin inflammation) plays a key role in NM‐induced cutaneous inflammation. Herein, we initially confirmed that NM markedly promoted COX2 expression in vitro and in vivo. NM also increased NOD‐like receptor family pyrin domain containing 3 (NLRP3) expression, caspase‐1 activity, and interleukin‐1β (IL‐1β) release. Notably, treatment with a caspase‐1 inhibitor (zYVAD‐fmk), NLRP3 inhibitor (MCC950), and NLRP3 or caspase‐1 siRNA attenuated NM‐induced NLRP3 inflammasome activation, with subsequent suppression of COX2 expression and IL‐1β release in keratinocytes. Meanwhile, NM increased mitochondrial reactive oxygen species (mtROS) and decreased manganese superoxide dismutase 2 (SOD2) and sirtuin 3 (SIRT3) activities. Mito‐TEMPO (a mtROS scavenger) ameliorated NM‐caused NLRP3 inflammasome activation in keratinocytes. Moreover, VD3 improved SIRT3 and SOD2 activities, decreased mtROS contents, inactivated the NLRP3 inflammasome, and attenuated cutaneous inflammation induced by NM in vitro and in vivo. The beneficial activity of VD3 against NM‐triggered cutaneous inflammation was enhanced by the inhibitors of IL‐1, mtROS, NLRP3, caspase‐1, and NLRP3 or caspase‐1 siRNAs, which was abolished in SIRT3 inhibitor or SIRT3 siRNA‐treated keratinocytes and skins from SIRT3−/− mice. In conclusion, VD3 ameliorated NM‐induced cutaneous inflammation by inactivating the NLRP3 inflammasome, which was partially mediated through the SIRT3–SOD2–mtROS signaling pathway.https://doi.org/10.1002/ctm2.312cutaneous inflammationnitrogen mustardNLRP3 inflammasomeSIRT3vitamin D3 |
| spellingShingle | Xunhu Dong Ying He Feng Ye Yuanpeng Zhao Jin Cheng Jingsong Xiao Wenpei Yu Jiqing Zhao Yan Sai Guorong Dan Mingliang Chen Zhongmin Zou Vitamin D3 ameliorates nitrogen mustard‐induced cutaneous inflammation by inactivating the NLRP3 inflammasome through the SIRT3–SOD2–mtROS signaling pathway Clinical and Translational Medicine cutaneous inflammation nitrogen mustard NLRP3 inflammasome SIRT3 vitamin D3 |
| title | Vitamin D3 ameliorates nitrogen mustard‐induced cutaneous inflammation by inactivating the NLRP3 inflammasome through the SIRT3–SOD2–mtROS signaling pathway |
| title_full | Vitamin D3 ameliorates nitrogen mustard‐induced cutaneous inflammation by inactivating the NLRP3 inflammasome through the SIRT3–SOD2–mtROS signaling pathway |
| title_fullStr | Vitamin D3 ameliorates nitrogen mustard‐induced cutaneous inflammation by inactivating the NLRP3 inflammasome through the SIRT3–SOD2–mtROS signaling pathway |
| title_full_unstemmed | Vitamin D3 ameliorates nitrogen mustard‐induced cutaneous inflammation by inactivating the NLRP3 inflammasome through the SIRT3–SOD2–mtROS signaling pathway |
| title_short | Vitamin D3 ameliorates nitrogen mustard‐induced cutaneous inflammation by inactivating the NLRP3 inflammasome through the SIRT3–SOD2–mtROS signaling pathway |
| title_sort | vitamin d3 ameliorates nitrogen mustard induced cutaneous inflammation by inactivating the nlrp3 inflammasome through the sirt3 sod2 mtros signaling pathway |
| topic | cutaneous inflammation nitrogen mustard NLRP3 inflammasome SIRT3 vitamin D3 |
| url | https://doi.org/10.1002/ctm2.312 |
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