Vitamin D receptor interacts with NLRP3 to restrict the allergic response

Huang, Hung‐Yu; Hong, Ji Yeon; Wu, Yanling; Wang, E-Y; Zq, Liu; Cheng, B-H; Lu, Mi; Zg, Liu; Yang, P-C.; Zheng, P-Y

doi:10.1111/cei.13164

Cited by 19 publications

(10 citation statements)

References 26 publications

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“…Vitamin D has been shown to inhibit the NLRP3 inflammasome either by direct binding between NLRP3 and VDR ( 26 ) or via VDR signaling-mediated inhibition of cytokine secretion ( 27 ). We measured the protein expression of NLRP3 and its downstream factors such as gasdermin D, caspase-1, and IL-18 in primary trophoblasts isolated from male and female placentae from normal-weight and obese women, and further assessed the effect of calcitriol in that context.…”

Section: Resultsmentioning

confidence: 99%

“…Excessive activation of the NLRP3 inflammasome has been shown to lead to diabetes, atherosclerosis, and obesity-induced insulin resistance ( 25 ). Vitamin D has been found to inhibit the NLRP3 inflammasome either by direct binding between NLRP3 and the Vitamin D receptor (VDR) ( 26 ) or via VDR signaling-mediated inhibition of cytokine secretion ( 27 ). However, the specific role of VitD in maternal obesity-mediated placental inflammation remains understudied.…”

Section: Introductionmentioning

confidence: 99%

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Vitamin D Supplementation Improves Mitochondrial Function and Reduces Inflammation in Placentae of Obese Women

et al. 2022

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BackgroundAbout 30% of women entering pregnancy in the US are obese. We have previously reported mitochondrial dysregulation and increased inflammation in the placentae of obese women. Vitamin D (VitD) is a major player in calcium uptake and was shown to modulate mitochondrial respiration and the immune/inflammation system. Studies show decreased VitD levels in obese individuals; however, the effect of maternal obesity on VitD metabolism and its association with placental function remains understudied.MethodsMaternal and cord blood plasma and placental samples were collected upon C-section from normal-weight (NW, body mass index [BMI]<25) and obese (OB, BMI>30) women with uncomplicated pregnancies at term. We measured 25(OH)D3 (calcidiol) levels in maternal and cord blood plasma using ELISA. We assessed the expression of CYP27B1, an activator of calcidiol, and Vitamin D receptor (VDR) in placentae from NW and OB, and women with gestational diabetes and preeclampsia. In addition, we examined the effects of VitD supplementation on mitochondrial function and inflammation in trophoblasts from NW and OB, using the Seahorse Bioanalyzer and Western blot, respectively.ResultsVitamin D levels in blood from OB but not NW women and in cord blood from babies born to NW and OB women showed a significant inverse correlation with maternal pre-pregnancy BMI (r=-0.50, p<0.1 and r=-0.55, p=0.004 respectively). Cord plasma VitD levels showed a positive correlation with placental efficiency, i.e., the ratio between fetal and placental weight, as well as with maternal blood VitD levels (r=0.69 and 0.83 respectively, p<0.00). While we found no changes in CYP27B1 in OB vs. NW women, VDR expression were decreased by 50% (p<0.03) independent of fetal sex. No changes in VDR expression relative to BMI-matched controls were observed in the placentae of women with gestational diabetes or preeclampsia. Cytotrophoblasts isolated from placentae of OB women showed a dose-dependent increase in VDR expression after 24-hour treatment with calcitriol (10 nM and 100 nM), an active form of VitD. Trophoblasts isolated from OB women and treated with calcitriol improved mitochondrial respiration (p<0.05). We also found a two-fold increase in expression of the NLRP3 inflammasome and the pro-inflammatory cytokine IL-18 in trophoblasts isolated from placentae of OB women (p<0.05), with IL-18 expression being reversed by calcitriol treatment (100 nM).ConclusionsWe show that VitD deficiency is at least partially responsible for mitochondrial dysfunction and increased inflammation in the placentae of obese women. Vitamin D supplementation could be beneficial in improving placental dysfunction seen in obese women.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Vitamin D Supplementation Improves Mitochondrial Function and Reduces Inflammation in Placentae of Obese Women

et al. 2022

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“…An early controversy focussed on whether the pro-type 2 adjuvant activity of alum is dependent on its ability to activate the NLRP3 inflammasome (33, 34). Subsequently, a variety of studies have found that NLRP3 either promotes (35–37) or restricts (31, 38) allergic responses and Th2 cells. Most recently, Perrson et al demonstrated a profound ability of Charcot-Leyden crystals to promote type 2 immunity but the ability of the crystals to activate the NLRP3 inflammasome was not required for the adjuvant effect (39).…”

Section: Discussionmentioning

confidence: 99%

Inflammasome-Independent Role for NLRP3 in Controlling Innate Antihelminth Immunity and Tissue Repair in the Lung

Chenery

Alhallaf

Khudhair

et al. 2019

The Journal of Immunology

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Alternatively activated macrophages are essential effector cells during type 2 immunity and tissue repair following helminth infections. We previously showed that Ym1, an alternative activation marker, can drive innate IL-1R-dependent neutrophil recruitment during infection with the lung-migrating nematode, Nippostrongylus brasiliensis, suggesting a potential role for the inflammasome in the IL-1-mediated innate response to infection. Although inflammasome proteins such as NLRP3 have important proinflammatory functions in macrophages, their role during type 2 responses and repair are less defined. We therefore infected Nlrp3 2/2 mice with N. brasiliensis. Unexpectedly, compared with wild-type (WT) mice, infected Nlrp3 2/2 mice had increased neutrophilia and eosinophilia, correlating with enhanced worm killing but at the expense of increased tissue damage and delayed lung repair. Transcriptional profiling showed that infected Nlrp3 2/2 mice exhibited elevated type 2 gene expression compared with WT mice. Notably, inflammasome activation was not evident early postinfection with N. brasiliensis, and in contrast to Nlrp3 2/2 mice, antihelminth responses were unaffected in caspase-1/11-deficient or WT mice treated with the NLRP3-specific inhibitor MCC950. Together these data suggest that NLRP3 has a role in constraining lung neutrophilia, helminth killing, and type 2 immune responses in an inflammasome-independent manner.

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“…For example, VDR inhibits caspase activation, generation of mature IL-1β, and GSDMD-mediated pyroptosis in a murine model of kidney injury, as well as human tubular epithelial cells [ 143 , 144 ]. VDR can physically interact with NLRP3 [ 144 , 145 ]; the ligand-binding domain of VDR and the amino-terminal pyrin domain of NLRP3 are required for complex formation [ 144 ]. The VDR-NLRP3 interaction prevents the inflammasome function in both murine and human macrophages [ 144 ].…”

Section: Current Status Of Knowledgementioning

confidence: 99%

Lung-Centric Inflammation of COVID-19: Potential Modulation by Vitamin D

et al. 2021

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SARS-CoV-2 infects the respiratory tract and leads to the disease entity, COVID-19. Accordingly, the lungs bear the greatest pathologic burden with the major cause of death being respiratory failure. However, organs remote from the initial site of infection (e.g., kidney, heart) are not spared, particularly in severe and fatal cases. Emerging evidence indicates that an excessive inflammatory response coupled with a diminished antiviral defense is pivotal in the initiation and development of COVID-19. A common finding in autopsy specimens is the presence of thrombi in the lungs as well as remote organs, indicative of immunothrombosis. Herein, the role of SARS-CoV-2 in lung inflammation and associated sequelae are reviewed with an emphasis on immunothrombosis. In as much as vitamin D is touted as a supplement to conventional therapies of COVID-19, the impact of this vitamin at various junctures of COVID-19 pathogenesis is also addressed.

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Vitamin D receptor interacts with NLRP3 to restrict the allergic response

Cited by 19 publications

References 26 publications

Vitamin D Supplementation Improves Mitochondrial Function and Reduces Inflammation in Placentae of Obese Women

Vitamin D Supplementation Improves Mitochondrial Function and Reduces Inflammation in Placentae of Obese Women

Inflammasome-Independent Role for NLRP3 in Controlling Innate Antihelminth Immunity and Tissue Repair in the Lung

Lung-Centric Inflammation of COVID-19: Potential Modulation by Vitamin D

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