Vitamin D3 ameliorates nitrogen mustard-induced cutaneous inflammation by inactivating the NLRP3 inflammasome through the SIRT3-SOD2-mtROS signaling pathway.

Published on Feb 1, 2021in Clinical and translational medicine11.492
· DOI :10.1002/CTM2.312
Xunhu Dong3
Estimated H-index: 3
(Third Military Medical University),
Ying He1
Estimated H-index: 1
(Third Military Medical University)
+ 9 AuthorsZhongmin Zou20
Estimated H-index: 20
(Third Military Medical University)
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.
#1Hai-Long Li (Soochow University (Suzhou))H-Index: 2
#2Jae-Rin Lee (SKKU: Sungkyunkwan University)H-Index: 12
Last. Yong-Doo Park (THU: Tsinghua University)H-Index: 19
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AbstractIn this study, we aimed to identify critical factors associated with superoxide dismutase 2 (SOD2) in human keratinocytes through gene and protein expression profiling approaches. After rec...
#1Gabriella Wahler (RU: Rutgers University)H-Index: 1
#2Diane E. Heck (NYMC: New York Medical College)H-Index: 4
Last. Laurie B. Joseph (RU: Rutgers University)H-Index: 13
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Abstract Nitrogen mustard (NM) is a highly reactive bifunctional alkylating agent that induces inflammation, edema and blistering in skin. An important mechanism mediating the action of NM and related mustards is oxidative stress. In these studies a modified murine patch-test model was used to analyze DNA damage and the antioxidant/stress response following NM exposure in isolated epidermis. NM (20 μmol) was applied to glass microfiber filters affixed to a shaved dorsal region of skin of CD-1 mi...
#1Feng YeH-Index: 8
#2Qinya ZengH-Index: 1
Last. Zhongmin ZouH-Index: 20
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Abstract Transcription factor activator protein (AP)-1 can be activated in nitrogen-mustard-injured mouse skin, and is thought to participate in the inflammatory response. AP-1 consists of homo- or heterodimers of Fos [c-Fos, Fos-B, fos-related antigen (Fra)-1 and Fra-2] and Jun (c-Jun, JunB and JunD) family members, and information about their expression, location and function are still unclear. In nitrogen-mustard-exposed mouse skin, we found p-ERK activation increased Fra-1 and FosB. Unlike t...
#1Zhenning Liu (PRC: China Medical University (PRC))H-Index: 1
#2Xiaofeng Wang (PRC: China Medical University (PRC))H-Index: 1
Last. Min Zhao (PRC: China Medical University (PRC))H-Index: 1
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In addition to the lung, the liver is considered another major target for paraquat (PQ) poisoning. Hydrogen sulfide (H2S) has been demonstrated to be effective in the inhibition of oxidative stress and inflammation. The aim of this study was to investigate the protective effect of exogenous H2S against PQ-induced acute liver injury. The acute liver injury model was established by a single intraperitoneal injection of PQ, evidenced by histological alteration and elevated serum aminotransferase le...
#1Zebing Rao (Nanjing Medical University)H-Index: 1
#2Xin Chen (Nanjing Medical University)H-Index: 1
Last. Shuo Yang (Nanjing Medical University)H-Index: 2
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Abstract The NLRP3 inflammasome is a multiprotein oligomer responsible for activation of the inflammatory response by promoting the maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18. Dysregulation of this inflammasome has been linked to several autoimmune diseases, indicating that NLRP3 is tightly regulated to prevent aberrant activation. The regulation of NLRP3 activation remains unclear. Here, we report the identification of vitamin D receptor (VDR) as a negative regul...
#1Hao Li (Guangxi Medical University)H-Index: 3
#2Xinghua Zhong (Guangxi Medical University)H-Index: 3
Last. Qi Wang (Sichuan University)H-Index: 10
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Vitamin D has been known to have important regulatory functions in inflammation and immune response and shows inhibitory effects on experimental periodontitis in animal models. However, the potential mechanism has yet to be clarified. Recent studies have highlighted Aryl hydrocarbon receptor (AhR) and its downstream signaling as a crucial regulator of immune homeostasis and inflammatory regulation. Objective: This study aimed to clarify the effect of 1,25-dihydroxyvitamin D3 (VD3) on experimenta...
#1Azahara Rodríguez-Luna (University of Seville)H-Index: 7
#2Javier Ávila-Román (University of Seville)H-Index: 12
Last. Elena Talero (University of Seville)H-Index: 22
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Excessive exposure to ultraviolet (UV) radiation is the main risk factor to develop skin pathologies or cancer because it encourages oxidative condition and skin inflammation. In this sense, strategies for its prevention are currently being evaluated. Natural products such as carotenoids or polyphenols, which are abundant in the marine environment, have been used in the prevention of oxidative stress due to their demonstrated antioxidant activities. Nevertheless, the anti-inflammatory activity a...
#1Karen V. Swanson (UNC: University of North Carolina at Chapel Hill)H-Index: 16
#2Meng Deng (UNC: University of North Carolina at Chapel Hill)H-Index: 13
Last. Jenny P-Y TingH-Index: 10
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NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflam...
#1Angelo V. Marzano (University of Milan)H-Index: 47
#2Alex G. Ortega-Loayza (OHSU: Oregon Health & Science University)H-Index: 17
Last. Massimo Cugno (University of Milan)H-Index: 62
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Neutrophil-mediated skin diseases, originally named neutrophilic dermatoses, are a group of conditions due to an altered neutrophil recruitment and activation, characterized by polymorphic cutaneous manifestations with possible internal organ involvement. Although a number of diseases are included in this setting, the two prototypic forms are pyoderma gangrenosum and Sweet’s syndrome which usually present with skin ulcers and plaque-type lesions, respectively. They have central features signific...
#1Lili Xin (Soochow University (Suzhou))H-Index: 9
#2Bizhong Che (Soochow University (Taiwan))H-Index: 5
Last. Zengli Zhang (Soochow University (Taiwan))H-Index: 1
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Vitamin D3 is reported to be involved in the regulation of inflammatory processes. In this study, biomarkers related to oxidative stress and inflammation were investigated to clarify the protective effects and possible mechanism of 1,25-dihydroxy vitamin D3 (1,25-(OH)2D3) on PM2.5-induced inflammatory response. In the in vitro study using human bronchial epithelial (HBE) cells, aqueous extracts of PM2.5 could induce oxidative damage which is characterized by significant increases in production o...
Cited By1
#1Wenpei Yu (Third Military Medical University)H-Index: 1
#2Xunhu Dong (Third Military Medical University)H-Index: 3
Last. Zhongmin Zou (Third Military Medical University)H-Index: 20
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Abstract null null Respiratory system injury is the main cause of mortality for nitrogen mustard (NM)-induced damage. Previous studies indicate that reactive oxygen species (ROS) participates in NM-mediated respiratory injuries, but the detailed mechanism is not quite clear. Human bronchial epithelial cell lines 16HBE and BEAS-2B were treated with HN2, a type of NM. In detail, it was shown that HN2 treatment induced impaired cell viability, excessive mitochondrial ROS production and enhanced cel...
#1Liyang LiH-Index: 2
#2Ruixue Qi (Fudan University Shanghai Medical College)H-Index: 1
Last. Xiangdong Wang (Fudan University Shanghai Medical College)H-Index: 58
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