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; 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.

RETRACTED: Macrophage SAMSN1 protects against sepsis-induced acute lung injury in mice

“…In addition, WBCs and the pro-inflammatory cytokines also contribute to reactive oxygen species (ROS) overproduction and oxidative damage [ 5 , 6 ]. Both pro-inflammatory cytokines and ROS are potential activators of nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome, which is consistent of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1, and promotes the maturation and release of pro-inflammatory cytokines (e.g., IL-1β and IL-18) [ [7] , [8] , [9] , [10] ]. Macrophages are the dominant inflammatory cells in the lungs, and play critical roles in sepsis-induced inflammation, oxidative stress and ALI [ 11 ].…”

Krill Oil Inhibits NLRP3 Inflammasome Activation in the Prevention of the Pathological Injuries of Diabetic Cardiomyopathy

“…Collectively, these studies have demonstrated a positive feedback interaction between SIRT3 and PGC-1α, providing SIRT3/PGC-1α activation as a viable strategy for the intervention of DCM. Moreover, SIRT3 has been reported to be a crucial negative regulator of NLRP3 [40][41][42][43]. Mechanistically, SIRT3 deacetylates SOD2, leading to SOD2 activation, which impairs NLRP3 inflammasome assembly and activation [41].…”

Potential biomarkers and targets of mitochondrial dynamics

“… 125 , 126 , 129 Vitamin D3 downregulated mitochondrial ROS and related participants, for example, cyclooxygenase‐2, superoxide dismutase 2, NOD‐like receptor family pyrin domain containing 3, caspase‐1, SIRT3, and interleukin‐1β. 130 Changes in mitochondrial proteins and functions were also noticed in pulmonary arterial hypertension (PAH) and COPD. 37 , 131 , 132 Disease‐specific proteins related to mitochondrial function were identified from proteomic profiles of lung cancer, PAH, and COPD clinically and experimentally.…”

“… 127,128 Anticancer drugs inhibit the proliferation of lung cancer cells through targeting either mitochondrial bioenergetics, mitochondrial ROS production, or pyruvate dehydrogenase kinase activity (Figure 5C). 125,126,129 Vitamin D3 downregulated mitochondrial ROS and related participants, for example, cyclooxygenase‐2, superoxide dismutase 2, NOD‐like receptor family pyrin domain containing 3, caspase‐1, SIRT3, and interleukin‐1β 130 . Changes in mitochondrial proteins and functions were also noticed in pulmonary arterial hypertension (PAH) and COPD 37,131,132 .…”