Thioredoxin-Interacting Protein (TXNIP) Associated NLRP3 Inflammasome Activation in Human Alzheimer’s Disease Brain

Abstract Alzheimer’s disease (AD) is a progressive, late-onset dementia with no effective treatment available. Recent studies suggest that AD pathology is driven by age-related changes in metabolism. Alterations in metabolism, such as placing patients on a ketogenic diet, can alter cognition by an unknown mechanism. One of the ketone bodies produced as a result of ketogenesis, β-hydroxybutyrate (BHB), is known to inhibit NLRP3 inflammasome activation. Therefore, we tested if BHB inhibition of the NLRP3 inflammasome reduces overall AD pathology in the 5XFAD mouse model of AD. Here, we find BHB levels are lower in red blood cells and brain parenchyma of AD patients when compared with non-AD controls. Furthermore, exogenous BHB administration reduced plaque formation, microgliosis, apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc) speck formation, and caspase-1 activation in the 5XFAD mouse model of AD. Taken together, our findings demonstrate that BHB reduces AD pathology by inhibiting NLRP3 inflammasome activation. Additionally, our data suggest dietary or pharmacological approaches to increase BHB levels as promising therapeutic strategies for AD.

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TXNIP regulates age-associated neuroinflammation: Implication in Alzheimer’s disease

10.21203/rs.3.rs-25794/v1 ◽

2020 ◽

Author(s):

Saifudeen Ismael ◽

Sanaz Nasoohi ◽

Arum Yoo ◽

Lexiao Li ◽

Khurram Aslam ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Nlrp3 Inflammasome ◽

Experimental Studies ◽

Inflammasome Activation ◽

Control Analysis ◽

Age Related ◽

Nlrp3 Inflammasome Activation ◽

Thioredoxin System

Abstract Background Immune system hypersensitivity with aging is believed to contribute to mental frailty in elderlies. This is postulated to arise from accumulation of oxidative molecular patterns. Solid evidences delineates thioredoxin interacting protein (TXNIP), an inducible protein involved in oxidative stress, is essential for NOD-like receptor pyrin domain containing-3 (NLRP3)-inflammasome activation which intimately connects “inflammaging” to senile cognitive decline. This study aims to fundamentally explore the plausible involvement of TXNIP/NLRP3 inflammasome pathway in senile dementia and the typical Alzhemier’s disease. Methods In experimental studies cerebral samples from gender-matched mice were compared for TXNIP/NLRP3 inflammasome activation and klotho depletion, through immunoblotting and immunostaining in different life span points. In aged males, genetic or pharmacological ablation of TXNIP were then used to determine effects on cognitive decline and sensorimotor frailty in morris water maze, novel object recognition test and gait control analysis. Immunoblotting/staining experiments were also performed on human postmortem aged hippocampal specimens and 5XFAD transgenic mice, to ultimately address Alzheimer’s disease (AD) as the most age related dementia. Results According to our preclinical studies, cerebral TXNIP was significantly upregulated in aged animals, paralleled by the NLRP3-inflammasome over-activity in both sexes, and closely associated klotho depletion in aged males. TXNIP knock-out reversed age-related NLRP3-hyperactivity and enhanced thioredoxin (TRX) levels in aged brains. Further, pharmacological TXNIP inhibition replicated the TXNIP/NLRP3-inflammasome downregulation in aged animals, with FOXO-1 and mTOR upregulation. These alterations concurred with substantial improvements in both cognitive and sensorimotor abilities. Moreover, our immunostaining shows a significant increase of TXNIP in transgenic 5XFAD mice brain and TXNIP/NLRP3-inflammasome activity in AD human postmortem hippocampal specimens, in proximity of p-tau tangles and β-amyloid plaques. Conclusion Together, these findings substantiate the pivotal role of TXNIP to drive inflammging in parallel with klotho depletion and functional decline. TXNIP co-localization with hallmarks of AD pathology is further supportive of potential mechanistic links between TXNIP and AD. Unraveling new information on upstream pathways, these data support modulating thioredoxin system as a potential approach to decelerate senile frailty.

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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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