Uric acid drives intestinal barrier dysfunction through TSPO-mediated NLRP3 inflammasome activation

2020 ◽  
Author(s):  
Qiulan Lv ◽  
Daxing Xu ◽  
Jinfeng Ma ◽  
Yan Wang ◽  
Xiaomin Yang ◽  
...  
Keyword(s):  
Uric Acid ◽  
Nlrp3 Inflammasome ◽  
Intestinal Barrier ◽  
Inflammasome Activation ◽  
Barrier Dysfunction ◽  
Intestinal Barrier Dysfunction ◽  
Nlrp3 Inflammasome Activation

scholarly journals Association of Hyperuricemia With Immune Disorders and Intestinal Barrier Dysfunction

2020 ◽  
Vol 11 ◽  
Author(s):  
Qiulan Lv ◽  
Daxing Xu ◽  
Xuezhi Zhang ◽  
Xiaomin Yang ◽  
Peng Zhao ◽  
...  
Keyword(s):  
Uric Acid ◽  
Gut Microbiota ◽  
Intestinal Barrier ◽  
Urate Oxidase ◽  
Intestinal Immunity ◽  
Immune Disorders ◽  
Barrier Dysfunction ◽  
Intestinal Barrier Dysfunction ◽  
Gut Barrier Function ◽  
Tnf Α

BackgroundMore than 30–40% of uric acid is excreted via the intestine, and the dysfunction of intestinal epithelium disrupts uric acid excretion. The involvement of gut microbiota in hyperuricemia has been reported in previous studies, but the changes and mechanisms of intestinal immunity in hyperuricemia are still unknown.MethodsThis study developed a urate oxidase (Uox)-knockout (Uox–/–) mouse model for hyperuricemia using CRISPR/Cas9 technology. The lipometabolism was assessed by measuring changes in biochemical indicators. Furthermore, 4-kDa fluorescein isothiocyanate–labeled dextran was used to assess gut barrier function. Also, 16S rRNA sequencing was performed to examine the changes in gut microbiota in mouse feces. RNA sequencing, Western blot, Q-PCR, ELISA, and immunohistochemical analysis were used for measuring gene transcription, the number of immune cells, and the levels of cytokines in intestinal tissues, serum, kidney, liver, pancreas, and vascellum.ResultsThis study showed that the abundance of inflammation-related microbiota increased in hyperuricemic mice. The microbial pattern recognition–associated Toll-like receptor pathway and inflammation-associated TNF and NF-kappa B signaling pathways were significantly enriched. The increased abundance of inflammation-related microbiota resulted in immune disorders and intestinal barrier dysfunction by upregulating TLR2/4/5 and promoting the release of IL-1β and TNF-α. The levels of epithelial tight junction proteins occludin and claudin-1 decreased. The expression of the pro-apoptotic gene Bax increased. The levels of LPS and TNF-α in systemic circulation increased in hyperuricemic mice. A positive correlation was observed between the increase in intestinal permeability and serum levels of uric acid.ConclusionHyperuricemia was characterized by dysregulated intestinal immunity, compromised intestinal barrier, and systemic inflammation. These findings might serve as a basis for future novel therapeutic interventions for hyperuricemia.

scholarly journals Staphylococcal Enterotoxin A Induces Intestinal Barrier Dysfunction and Activates NLRP3 Inflammasome via NF-κB/MAPK Signaling Pathways in Mice

Toxins ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 29
Author(s):  
Chunmei Liu ◽  
Kunmei Chi ◽  
Meng Yang ◽  
Na Guo
Keyword(s):  
Signaling Pathways ◽  
Nlrp3 Inflammasome ◽  
Intestinal Barrier ◽  
Mapk Signaling ◽  
Staphylococcal Enterotoxin ◽  
Foodborne Diseases ◽  
Staphylococcal Enterotoxin A ◽  
Barrier Dysfunction ◽  
Intestinal Barrier Dysfunction ◽  
Mapk Signaling Pathways

Staphylococcal enterotoxin A (SEA), the toxin protein secreted by Staphylococcus aureus, can cause staphylococcal food poisoning outbreaks and seriously threaten global public health. However, little is known about the pathogenesis of SEA in staphylococcal foodborne diseases. In this study, the effect of SEA on intestinal barrier injury and NLRP3 inflammasome activation was investigated by exposing BALB/c mice to SEA with increasing doses and a potential toxic mechanism was elucidated. Our findings suggested that SEA exposure provoked villi injury and suppressed the expression of ZO-1 and occludin proteins, thereby inducing intestinal barrier dysfunction and small intestinal injury in mice. Concurrently, SEA significantly up-regulated the expression of NLRP3 inflammasome-associated proteins and triggered the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathways in jejunum tissues. Notably, selective inhibitors of MAPKs and NF-κB p65 ameliorated the activation of NLRP3 inflammasome stimulated by SEA, which further indicated that SEA could activate NLRP3 inflammasome through NF-κB/MAPK pathways. In summary, SEA was first confirmed to induce intestinal barrier dysfunction and activate NLRP3 inflammasome via NF-κB/MAPK signaling pathways. These findings will contribute to a more comprehensive understanding of the pathogenesis of SEA and related drug-screening for the treatment and prevention of bacteriotoxin-caused foodborne diseases via targeting specific pathways.

scholarly journals Methyl Gallate Improves Hyperuricemia Nephropathy Mice Through Inhibiting NLRP3 Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng Liu ◽  
Wen Wang ◽  
Qiang Li ◽  
Xin Hu ◽  
Bingyong Xu ◽  
...  
Keyword(s):  
Uric Acid ◽  
Nlrp3 Inflammasome ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Human Peripheral Blood ◽  
Collecting Duct ◽  
Potassium Oxide ◽  
Inflammasome Activation ◽  
Methyl Gallate ◽  
Nlrp3 Inflammasome Activation

Hyperuricemia nephropathy (HN) is a form of chronic tubulointerstitial inflammation, caused by the deposition of monosodium urate crystals (MSU) in the distal collecting duct and medullary interstitium, associated with a secondary inflammatory reaction. Numerous published reports indicated that NLRP3 inflammasome pathway play crucial roles in HN symptoms. The present study aims to investigate the protective effects of methyl gallate on HN mice and the underlying mechanisms. An HN model was established by intraperitoneal injection of potassium oxide (PO) to assess the effect of methyl gallate on renal histopathological changes, renal function, cytokine levels and expressions of NLRP3-related protein in HN mice. Moreover, in vitro models of lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDMs) and human peripheral blood mononuclear cells (PBMCs) were established to explore the mechanism of methyl gallate on NLRP3 inflammasome activation. The results showed that methyl gallate significantly ameliorated HN by inhibiting uric acid production and promoting uric acid excretion as well as ameliorating renal injury induced by NLRP3 activation. Mechanistically, methyl gallate is a direct NLRP3 inhibitor that inhibits NLRP3 inflammasome activation but has no effect on the activation of AIM2 or NLRC4 inflammasomes in macrophages. Furthermore, methyl gallate inhibited the assembly of NLRP3 inflammasomes by blocking the ROS over-generation and oligomerization of NLRP3. Methyl gallate was also active ex vivo against ATP-treated PBMCs and synovial fluid mononuclear cells from patients with gout. In conclusion, methyl gallate has a nephroprotective effect against PO-induced HN through blocking the oligomerization of NLRP3 and then exerting anti-inflammatory activity in the NLRP3-driven diseases.

LncRNA ANRIL promotes NLRP3 inflammasome activation in uric acid nephropathy through miR-122-5p/BRCC3 axis

Biochimie ◽  
2019 ◽  
Vol 157 ◽  
pp. 102-110 ◽  
Author(s):  
Jiacai Hu ◽  
Hao Wu ◽  
Daochun Wang ◽  
Zhijie Yang ◽  
Junjun Dong
Keyword(s):  
Uric Acid ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Uric Acid Nephropathy
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