The Absence of NLRP3-inflammasome Modulates Hepatic Fibrosis Progression, Lipid Metabolism, and Inflammation in KO NLRP3 Mice during Aging

Abstract

Aging is associated with metabolic changes and low-grade inflammation in several organs, which may be due to NLRP3 inflammasome activation. Methods: Here, we asked whether age-related liver changes such as lipid metabolism and fibrosis are reduced in aged mice lacking the NLRP3 inflammasome. We report reduced protein levels of lipid markers (MTP, FASN, DGAT1), SOD activity, oxidative stress marker PTPRG, and the fibrotic markers TPM2β, COL1-α1 associated with increased GATA4, in NLRP3 deficient mice. Fibrotic, lipid, and oxidative reduction in liver tissues of mice was more pronounced in those old KO NLRP3 mice than in the younger ones, despite their greater liver damage. These results suggest that absence of the NLRP3 inflammasome attenuates age-related liver fibrotic pathology in mice, suggesting that pharmacological targeting may be beneficial.

The Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK/Akt/mTOR Pathway

“…We also investigated whether NLRP3 inflammasome activation could be involved in TMAO-induced fibroblast proliferation. A variety of studies support the association of the NLRP3 inflammasome with fibrosis, TMAO, Akt and mTOR [22,23,[64][65][66][67]. Using NLRP3 and caspase-1 knockout cell lines, we found that the proliferative effect of TMAO on human renal fibroblasts is NLRP3 and caspase-1 dependent.…”

“…According to Artlett et al, chronically activated NLRP3 inflammasome leads to constant ECM synthesis and induction of fibrosis by maintaining fibroblasts in their activated state or by keeping a high level of TGF-β1 via IL-1β production [22,23]. Moreover, there is evidence that NLRP3 inflammasome has a role in lung [23] and liver [64] fibrosis. Regarding the effect of TMAO on NLRP3 inflammasome, it has been shown that the TMAO increases the activation of the NLRP3 inflammasome in carotid arteries of mice [65].…”

Ginsenoside Rg1 ameliorates aging‑induced liver fibrosis by inhibiting the NOX4/NLRP3 inflammasome in SAMP8 mice

“…Excessive ROS production is an important process for the activation of inflammasome complexes (70)(71)(72). The NLRP3 inflammasome has been reported to be extensively expressed in the liver (20,73). Previous studies have reported that the NLRP3 inflammasome was activated in the progression of alcoholic liver disease (ALD), and liver inflammation and steatosis were significantly improved in ALD mice with knocked out NLRP3 or caspase-1 expression (74,75).…”

“…These results also discovered that the arrangement of hepatocytes was abnormal and disordered and most of the cells appeared to have vacuole-like degeneration in the SAMP8 group, while Rg1 treatment showed a significant improvement in liver histopathology. In addition, the results discovered that NOX4/NLRP3 inflammasome signaling, which is closely associated with age-related liver injury and liver fibrosis ( 20 ), was significantly inhibited by Rg1 (5 and 10 mg/kg) treatment, especially in the Rg1 (10 mg/kg) group. These results suggested that Rg1 treatment may be effective in preventing aged-related injury and fibrosis in a dose-dependent manner, possibly by inhibiting NOX4 and the NLRP3 inflammasome.…”

“…Inflammasomes, which are large cytoplasmic multiprotein complexes, consist of NLR family pyrin domain containing (NLRP), a cytoplasmic pattern recognition receptor of caspase-1 and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC). According to the findings of previous studies, the NLRP3 inflammasome, a type of inflammasome ubiquitously expressed in numerous tissues, including the liver, was discovered to be involved in the evolution of liver fibrosis and the progression of liver injury and age-related liver disease ( 20 – 22 ). When activated by diverse irritants, such as ATP and cholesterol crystals, as well as bacterial, viral and fungal pathogens ( 23 , 24 ), the NLRP3 inflammasome responds to inflammation by promoting the maturation of a series of proinflammatory cytokines, such as IL-1β and IL-18 ( 25 ).…”