Thioredoxin-1 regulates IRE1α to ameliorate sepsis-induced NLRP3 inflammasome activation and oxidative stress in Raw 264.7 cell

Abstract Objective: Sepsis is life-threatening organ dysfunction caused by the dysregulated host response to infection. Endoplasmic reticulum stress (ERS)-mediated inositol-requiring enzyme 1 α (IRE1α) inflammatory signaling pathway is involved in sepsis. NLRP3 inflammasome plays a key role in the activation of caspase-1 and the maturation of IL-1β and IL-18, and finally enhances the inflammatory response. More and more evidences show that ERS is an endogenous trigger of NLRP3 inflammasome. Thioredoxin-1 (Trx-1) is a small ubiquitous thiol-1 protein with redox/inflammation modulatory properties relevant to sepsis pathogenesis. In this study, we investigated the role of Trx-1 in ERS mediated IRE1α/NLRP3 signaling pathway in Raw 264.7 cells. Methods: Raw 264.7 cells stimulated by LPS were used to construct an inflammation model of sepsis in vitro, and the expression of proteins related to the IRE1α/NLRP3 pathway was detected through using western blot and RT-PCR. The expression of IL-18 and IL-1β in cell supernatant was also measured by ELISA, and caspase 1 activity and ROS expression in cells were detected by kits. Results: Our study shows that IRE1α signaling pathway related to endoplasmic reticulum stress in sepsis can activate inflammation related genes, and stimulate to produce a large number of pro-IL-1β. At the same time, IRE1α can activate NLRP3 inflammasome and promote activation and maturation of pro-IL-1β. Finally leads to excessive inflammatory response and ROS release, and promotes the progress of sepsis. Conclusions: Trx-1 may inhibit NLRP3 activity and pro-IL-Iβ production by inhibit IRE1α pathway of ER stress. So as to inhibit inflammatory response and ROS of cells, and play a protective role in sepsis.

[1]  Xujie Wang,et al.  Exosomes from adipose-derived stem cells alleviate the inflammation and oxidative stress via regulating Nrf2/HO-1 axis in macrophages. , 2021, Free radical biology & medicine.

[2]  G. Karimi,et al.  Endoplasmic reticulum stress in doxorubicin-induced cardiotoxicity may be therapeutically targeted by natural and chemical compounds: A review. , 2020, Pharmacological research.

[3]  C. Stehlik,et al.  An overview of the non-canonical inflammasome. , 2020, Molecular aspects of medicine.

[4]  Rizwan Ahamed,et al.  Update on diagnosis and management of sepsis in cirrhosis: Current advances , 2020, World journal of hepatology.

[5]  Antonio J. Pérez-Pulido,et al.  Inhibition of the NLRP3 inflammasome prevents ovarian aging , 2020, Science Advances.

[6]  Shimin Zhao,et al.  The expression of thioredoxin-1 and inflammatory cytokines in patients with sepsis , 2020, Immunopharmacology and immunotoxicology.

[7]  J. Yodoi,et al.  Anti-allergic and Anti-inflammatory Effects and Molecular Mechanisms of Thioredoxin on Respiratory System Diseases. , 2019, Antioxidants & redox signaling.

[8]  W. Zhou,et al.  Correction to: endoplasmic reticulum stress may activate NLRP3 inflammasomes via TXNIP in preeclampsia , 2019, Cell and Tissue Research.

[9]  L. Singh,et al.  Auranofin Mediates Mitochondrial Dysregulation and Inflammatory Cell Death in Human Retinal Pigment Epithelial Cells: Implications of Retinal Neurodegenerative Diseases , 2019, Front. Neurosci..

[10]  A. von Deimling,et al.  Mutant IDH sensitizes gliomas to endoplasmic reticulum stress and triggers apoptosis by MicroRNA183-mediated inhibition of Semaphorin 3E. , 2019, Cancer research.

[11]  X. Ci,et al.  Oridonin attenuates carrageenan-induced pleurisy via activation of the KEAP-1/Nrf2 pathway and inhibition of the TXNIP/NLRP3 and NF-κB pathway in mice , 2019, Inflammopharmacology.

[12]  S. Naicker,et al.  Inhibition of IRE1α RNase activity reduces NLRP3 inflammasome assembly and processing of pro-IL1β , 2019, Cell Death & Disease.

[13]  Xiaoshuang Zhou,et al.  Brain-derived neurotrophic factor induces thioredoxin-1 expression through TrkB/Akt/CREB pathway in SH-SY5Y cells. , 2019, Biochimie.

[14]  L. Glimcher,et al.  The IRE1 ER stress sensor activates natural killer cell immunity in part by regulating c-Myc , 2019, Nature Immunology.

[15]  Zhiqiang Ma,et al.  Endoplasmic reticulum stress and NLRP3 inflammasome: Crosstalk in cardiovascular and metabolic disorders , 2019, Journal of cellular physiology.

[16]  S. Singh,et al.  Recent advances in biosensors for diagnosis and detection of sepsis: A comprehensive review. , 2019, Biosensors & bioelectronics.

[17]  Zhijian J. Chen,et al.  PtdIns4P on Dispersed Trans-Golgi Network Mediates NLRP3 Inflammasome Activation , 2018, Nature.

[18]  E. Alnemri,et al.  SUMO-mediated regulation of NLRP3 modulates inflammasome activity , 2018, Nature Communications.

[19]  A. Nègre-Salvayre,et al.  A thioredoxin-mimetic peptide exerts potent anti-inflammatory, antioxidant, and atheroprotective effects in ApoE2.Ki mice fed high fat diet , 2018, Cardiovascular research.

[20]  Judith A. Smith.  Regulation of Cytokine Production by the Unfolded Protein Response; Implications for Infection and Autoimmunity , 2018, Front. Immunol..

[21]  Chaoqian Xu,et al.  Melatonin prevents endothelial cell pyroptosis via regulation of long noncoding RNA MEG3/miR‐223/NLRP3 axis , 2018, Journal of pineal research.

[22]  W. Xue,et al.  NLRP3 Phosphorylation Is an Essential Priming Event for Inflammasome Activation. , 2017, Molecular cell.

[23]  Shuai Jiang,et al.  AMPK orchestrates an elaborate cascade protecting tissue from fibrosis and aging , 2017, Ageing Research Reviews.

[24]  G. Neigh,et al.  Checks and balances: The glucocorticoid receptor and NFĸB in good times and bad , 2017, Frontiers in Neuroendocrinology.

[25]  Xiaoshuang Zhou,et al.  The Role of Thioredoxin-1 in Suppression Sepsis Through Inhibiting Mitochondrial-Induced Apoptosis in Spleen , 2017, Shock.

[26]  Zhiqiang Ma,et al.  Utilizing melatonin to combat bacterial infections and septic injury , 2017, British journal of pharmacology.

[27]  Chenggong Yu,et al.  Plant Lectins Activate the NLRP3 Inflammasome To Promote Inflammatory Disorders , 2017, The Journal of Immunology.

[28]  Xiaoshuang Zhou,et al.  Thioredoxin-1 Increases Survival in Sepsis by Inflammatory Response Through Suppressing Endoplasmic Reticulum Stress , 2016, Shock.

[29]  Randal J. Kaufman,et al.  The unfolded protein response in immunity and inflammation , 2016, Nature Reviews Immunology.

[30]  S. Ryter,et al.  Regulation and Function of the Nucleotide Binding Domain Leucine-Rich Repeat-Containing Receptor, Pyrin Domain-Containing-3 Inflammasome in Lung Disease. , 2016, American journal of respiratory cell and molecular biology.

[31]  Chuan-Qi Zhong,et al.  Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion , 2015, Cell Research.

[32]  Xin-hua Yin,et al.  Cortistatin protects myocardium from endoplasmic reticulum stress induced apoptosis during sepsis , 2015, Molecular and Cellular Endocrinology.

[33]  Bao-lin Liu,et al.  Mangiferin inhibits endoplasmic reticulum stress-associated thioredoxin-interacting protein/NLRP3 inflammasome activation with regulation of AMPK in endothelial cells. , 2015, Metabolism: clinical and experimental.

[34]  R. Hegde,et al.  Regulation of basal cellular physiology by the homeostatic unfolded protein response , 2010, The Journal of cell biology.

[35]  S. Ban,et al.  Does thioredoxin-1 prevent mitochondria- and endoplasmic reticulum-mediated neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine? , 2007, Antioxidants & redox signaling.