Nod-like Receptor Protein 3 (NLRP3) Inflammasome Activation and Podocyte Injury via Thioredoxin-Interacting Protein (TXNIP) during Hyperhomocysteinemia

Inflammation plays a crucial part in hyperglycemia-induced myocardial damage. Hydrogen sulfide has been found to possess multiple biological activities in previous studies. This study investigated whether hydrogen sulfide conferred cardiac protection against damage in a diabetic rat model by inhibiting nucleotide-binding oligomerization domain-like receptor protein (NLRP) 3 inflammasome activation. Male animals were assigned to control, streptozotocin, streptozotocin + sodium hydrosulfide, and streptozotocin + DL-propargylglycine groups. Animals in the three streptozotocin groups were administrated 55 mg/kg streptozotocin by intraperitoneal injection. Streptozotocin + sodium hydrosulfide and streptozotocin + propargylglycine groups were treated with sodium hydrosulfide (56 μmol/kg) and propargylglycine (40 mg/kg), respectively, for four weeks. Estimation of fasting blood glucose, heart-weight/body-weight, cardiac function, and histopathological analysis, and measurement of myocardial enzymes were done to evaluate the degree of cardiac injury. In order to investigate the redox changes, the levels of total antioxidant capacity, malondialdehyde and lipid peroxidation, and the activities of superoxide dismutase, catalase, and glutathione peroxidase were assessed; the protein expression levels of Thioredoxin and Thioredoxin-interacting protein were measured in myocardial tissue. In addition, inflammatory reactions were assessed by measuring the concentration levels of interleukin-6, tumor necrosis factor-α, interleukin-1β, and interleukin-18 in serum and the expression levels of NLRP3 inflammasome complex-associated proteins in cardiac tissue. In the heart, hyperglycemia significantly induced cardiac dysfunction and injury, redox perturbation, and aggravation of inflammatory reactions. However, except for fasting blood glucose, treatment with sodium hydrosulfide significantly ameliorated these alterations, whereas treatment with propargylglycine further aggravated these alterations. This study highlights the protective properties of hydrogen sulfide against hyperglycemia-induced cardiac injury, and its possible mechanism was shown to involve negative regulation of Thioredoxin-interacting protein-mediated NLRP3 inflammasome activation. Impact statement Diabetic cardiomyopathy is a serious complication of diabetic patients, accompanied by chronic inflammation. The nucleotide-binding oligomerization domain-like receptor protein (NLRP) 3 inflammasome complex is involved in the progression of the inflammatory response of diabetes, including diabetic cardiomyopathy. Hydrogen sulfide (H2S) is a novel endogenous gas messenger. Several pieces of evidence have exhibited that H2S exerts anti-oxidant and anti-inflammatory activities against hyperglycemia-induced myocardial injury, but the mechanism remains unclear. The current study indicated that H2S protected the myocardium against hyperglycemia-induced injury by preventing Thioredoxin-interacting protein (TXNIP)-mediated NLRP3 inflammasome complex activation. The inhibition of TXNIP-mediated NLRP3 inflammasome complex would be an efficient therapy for H2S treatment in diabetic cardiomyocytes.

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Deletion of Thioredoxin-Interacting Protein (TXNIP) Abrogates High Fat Diet-Induced Retinal Leukostasis, Barrier Dysfunction and Microvascular Degeneration in a Mouse Obesity Model

International Journal of Molecular Sciences ◽

10.3390/ijms21113983 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3983 ◽

Cited By ~ 1

Author(s):

Islam N. Mohamed ◽

Nader Sheibani ◽

Azza B. El-Remessy

Keyword(s):

Adhesion Molecules ◽

Nlrp3 Inflammasome ◽

High Fat Diet ◽

Receptor Protein ◽

Inflammasome Activation ◽

High Fat ◽

Barrier Dysfunction ◽

Interacting Protein ◽

Thioredoxin Interacting Protein ◽

The Impact

We have shown that a high fat diet (HFD) induces the activation of retinal NOD-like receptor protein (NLRP3)-inflammasome that is associated with enhanced expression and interaction with thioredoxin-interacting protein (TXNIP). Here, the specific contribution of TXNIP and the impact of HFD on retinal leukostasis, barrier dysfunction and microvascular degeneration were investigated. Wild-type (WT) and TXNIP knockout (TKO) mice were fed with normal diet or 60% HFD for 8–18 weeks. TXNIP was overexpressed or silenced in human retinal endothelial cells (REC). At 8 weeks, HFD significantly induced retinal leukostasis and breakdown of the blood–retina barrier in WT mice, but not in TKO mice. In parallel, HFD also induced retinal expression of adhesion molecules and cleaved IL-1β in WT mice, which were also abrogated in TKO mice. In culture, TXNIP overexpression induced NLRP3, IL-1β, and adhesion molecules expression, while TXNIP silencing inhibited them. Blocking the IL-1β receptor significantly suppressed TXNIP-induced expression of NLRP3-inflammasome and adhesion molecules in HREC. Ex-vivo assay showed that leukocytes isolated from WT-HFD, but not from TKO-HFD, induced leukostasis and cell death. At 18 weeks, HFD triggered development of degenerated (acellular) capillaries and decreased branching density in WT but not in TKO mice. Together, HFD-induced obesity triggered early retinal leukostasis and microvascular dysfunction at least in part via TXNIP-NLRP3-inflammasome activation.

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Thioredoxin‐Interacting Protein Mediates Hcys‐induced NLRP3 Inflammasome Activation in Mouse Podocytes

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.704.7 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Justine Abais ◽

Krishna M. Boini ◽

Min Xia ◽

Pin‐Lan Li

Keyword(s):

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Interacting Protein ◽

Thioredoxin Interacting Protein ◽

Nlrp3 Inflammasome Activation

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MicroRNA-152 attenuates neuroinflammation in intracerebral hemorrhage by inhibiting thioredoxin interacting protein (TXNIP)-mediated NLRP3 inflammasome activation

International Immunopharmacology ◽

10.1016/j.intimp.2019.106141 ◽

2020 ◽

Vol 80 ◽

pp. 106141 ◽

Cited By ~ 2

Author(s):

Liuting Hu ◽

Heyu Zhang ◽

Bingyang Wang ◽

Qiang Ao ◽

Zhiyi He

Keyword(s):

Intracerebral Hemorrhage ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Interacting Protein ◽

Thioredoxin Interacting Protein ◽

Nlrp3 Inflammasome Activation

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Endoplasmic reticulum stress may activate NLRP3 inflammasomes via TXNIP in preeclampsia

10.1101/351650 ◽

2018 ◽

Author(s):

Yong Yang ◽

Jianxin Li ◽

Ting-Li Han ◽

Xiaobo Zhou ◽

Hongbo Qi ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Nlrp3 Inflammasome ◽

Critical Role ◽

Inflammasome Activation ◽

Interacting Protein ◽

Thioredoxin Interacting Protein ◽

Pyrin Domain ◽

Nlrp3 Inflammasome Activation ◽

Nlrp3 Inflammasomes

AbstractPreeclampsia (PE) development is often associated with placental immune and inflammatory dysregulation, as well as endoplasmic reticulum (ER) stress. However, the mechanisms linking ER stress and inflammatory dysregulation to PE have not been clarified. It has been reported that thioredoxin-interacting protein (TXNIP), which can bind with and activate the NLR family pyrin domain containing 3 (NLRP3) inflammasome, plays a critical role in immune regulation. Recent experimental evidence suggests that activated NLRP3 inflammasomes can activate interleukin-1β (IL-1β) production in the placenta of patients with PE. The objective of the current study was to explore if TXNIP plays a critical signaling role linking ER stress with NLRP3 inflammasome activation in PE. We hypothesised that ER stress would induce TXNIP production, which would bind with NLRP3 inflammasomes to activate IL-1β production. HTR8/SVneo cells were subjected to six hours hypoxia followed by six hours reoxygenation (H/R). These cells showed a higher protein level of NLRP3 and IL-1β, as well as a higher enzymatic activity of caspase-1, indicating enhanced inflammatory dysregulation and ER stress. Cells transfected with TXNIP siRNA showed reduced NLRP3 inflammasome activation. Cells treated with 4-phenylbutyric acid, an inhibitor of ER stress, showed a similar result. In addition, the outgrowth of explant with TXNIP lentivirus in H/R or Tunicamycin (inducers of ER stress) was also measured to verify our hypothesis. These findings demonstrated that TXNIP could influence inflammatory dysregulation by mediating ER stress and NLRP3 inflammasome activation in PE. This novel mechanism may further explain the inflammation observed at the maternal-fetal interface, which leads to placental dysfunction in a patient with PE.

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STS Protects Diabetic Glomerular Vascular Endothelial Barrier by Ameliorating EPC Dysfunction: Targeting RAGE-TXNIP-NLRP3 Inflammasome Pathway

10.21203/rs.3.rs-988095/v1 ◽

2021 ◽

Author(s):

Yan-Yan Heng ◽

Xiao-Yan Zhang ◽

Fei-Fei Wang ◽

Peng-Fei Zhang ◽

wei wei

Keyword(s):

Dna Damage ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Vascular Endothelial ◽

Urine Protein ◽

Interacting Protein ◽

Thioredoxin Interacting Protein ◽

Caspase 1 ◽

Pyrin Domain ◽

Nlrp3 Inflammasome Activation

Abstract Background: Glomerular endothelial cell (GEC) injury is one of the crucial causes of diabetic kidney disease (DKD). Endothelial progenitor cell (EPC) is the essential mechanism of vascular endothelial repair, which damages by diabetic pathology. Sodium Tanshinone Sulfonate ⅡA (STS) is known to protect endothelium, but the mechanism and the role in DKD need to be studied. Methods: EPC was treated with high glucose (HG), and thioredoxin interacting protein (TXNIP), NLR family pyrin domain containing 3 (NLRP3) inflammasome, DNA damage, proliferation, differentiation and senescence were detected; STS and EPC were intravenous injected into diabetic nude mice, the urine protein quantitation and urine protein/creatinine were detected; the Dil-labeled EPC was traced and the expression of TXNIP, caspase-1 (p20), p21, Ki67, CD31 were detected by fluorescence co-location in glomerulus.Results: We found that STS inhibited HG-induced TXNIP expression and NLRP3 inflammasome activation, catalase (CAT) inactivation, DNA damage, senescence； STS restored EPC proliferation and differentiation functions; advanced glycation end products (AGEs) produced in HG treated EPC supernatant, the receptor of AGE (RAGE) blocking inhibited TXNIP expression and NLRP3 inflammasome activation, which mimicked by STS. STS protected EPC functions in diabetic glomerular and enhanced EPC renal function amelioration. Conclusions: We concluded that STS watched CAT activity to prevent HG-induced EPC DNA damage, proliferation, differentiation dysfunction, accelerated senescence by inhibiting the RAGE-TXNIP-NLRP3 inflammasome-caspase-1 pathway.

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