Effects of mitochondrial reactive oxygen species-induced NLRP3 inflammasome activation on trichloroethylene-mediated kidney immune injury

Xie, Haibo; Peng, Jiale; Deng, Lihua; Ding, Yani; Zuo, Xulei; Wang, Feng; Wu, Yingliang; Zhang, Jiaxiang; Zhu, Qingsan

doi:10.1016/j.ecoenv.2022.114067

Cited by 11 publications

(5 citation statements)

References 31 publications

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“…While different from neurons, HEK cells are extensively characterized in the LRRK2 literature 25,26,44,80,81 , have been used as a model system to study the effects of LRRK2 mutations and display similar energetic demands of neurons that rely heavily on mitochondrial function [82][83][84] . We also strategically chose to evaluate toxicants linked to PD risk with structural dissimilarities but associated with mitochondrial dysfunction 13,19,47,[56][57][58][59][60]85 . However, we could not feasibly compare each in an in vivo model.…”

Section: Discussionmentioning

confidence: 99%

LRRK2 kinase inhibition protects against Parkinson’s disease-associated environmental toxicants

Ilieva,

Hoffman,

Ghalib

et al. 2024

Preprint

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Idiopathic Parkinson′s disease (PD) is epidemiologically linked with exposure to toxicants such as pesticides and solvents, which comprise a wide array of chemicals that pollute our environment. While most are structurally distinct, a common cellular target for their toxicity is mitochondrial dysfunction, a key pathological trigger involved in the selective vulnerability of dopaminergic neurons. We and others have shown that environmental mitochondrial toxicants such as the pesticides rotenone and paraquat, and the organic solvent trichloroethylene (TCE) appear to be influenced by the protein LRRK2, a genetic risk factor for PD. As LRRK2 mediates vesicular trafficking and influences endolysosomal function, we postulated that LRRK2 kinase activity may inhibit the autophagic removal of toxicant damaged mitochondria, resulting in elevated oxidative stress. Conversely, we suspected that inhibition of LRRK2, which has been shown to be protective against dopaminergic neurodegeneration caused by mitochondrial toxicants, would reduce the intracellular production of reactive oxygen species (ROS) and prevent mitochondrial toxicity from inducing cell death. To do this, we tested in vitro if genetic or pharmacologic inhibition of LRRK2 (MLi2) protected against ROS caused by four toxicants associated with PD risk — rotenone, paraquat, TCE, and tetrachloroethylene (PERC). In parallel, we assessed if LRRK2 inhibition with MLi2 could protect against TCE-induced toxicity in vivo, in a follow up study from our observation that TCE elevated LRRK2 kinase activity in the nigrostriatal tract of rats prior to dopaminergic neurodegeneration. We found that LRRK2 inhibition blocked toxicant-induced ROS and promoted mitophagy in vitro, and protected against dopaminergic neurodegeneration, neuroinflammation, and mitochondrial damage caused by TCE in vivo. We also found that cells with the LRRK2 G2019S mutation displayed exacerbated levels of toxicant induced ROS, but this was ameliorated by LRRK2 inhibition with MLi2. Collectively, these data support a role for LRRK2 in toxicant–induced mitochondrial dysfunction linked to PD risk through oxidative stress and the autophagic removal of damaged mitochondria.

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Section: Discussionmentioning

confidence: 99%

LRRK2 kinase inhibition protects against Parkinson’s disease-associated environmental toxicants

Ilieva,

Hoffman,

Ghalib

et al. 2024

Preprint

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“…However, research has shown that recombinant human IL-1 receptor antagonists (rhil-1RAs) can suppress NLRP3 inflammasome activation and IL-1β production ( 87 ). The NLRP3 inflammasome can be activated by MAMPs and DAMPs, and mitochondria-derived ROS (mtROS) are thought to be critical factors that promote this activation ( 88 , 89 ). An rhIl-1RA was demonstrated to significantly reduce pyroptosis by lowering ROS levels in ConA-induced mice and the production of NLRP3, active caspase-1, and IL-1β in hepatocytes ( Figure 2 ) ( 90 ).…”

Section: Inflammasomes and Pyroptosis In Aildsmentioning

confidence: 99%

Inflammasome and pyroptosis in autoimmune liver diseases

et al. 2023

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Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and IgG4-related sclerosing cholangitis (IgG4-SC) are the four main forms of autoimmune liver diseases (AILDs), which are all defined by an aberrant immune system attack on the liver. Most previous studies have shown that apoptosis and necrosis are the two major modes of hepatocyte death in AILDs. Recent studies have reported that inflammasome-mediated pyroptosis is critical for the inflammatory response and severity of liver injury in AILDs. This review summarizes our present understanding of inflammasome activation and function, as well as the connections among inflammasomes, pyroptosis, and AILDs, thus highlighting the shared features across the four disease models and gaps in our knowledge. In addition, we summarize the correlation among NLRP3 inflammasome activation in the liver-gut axis, liver injury, and intestinal barrier disruption in PBC and PSC. We summarize the differences in microbial and metabolic characteristics between PSC and IgG4-SC, and highlight the uniqueness of IgG4-SC. We explore the different roles of NLRP3 in acute and chronic cholestatic liver injury, as well as the complex and controversial crosstalk between various types of cell death in AILDs. We also discuss the most up-to-date developments in inflammasome- and pyroptosis-targeted medicines for autoimmune liver disorders.

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“…Another study indicated that NLRP3 deficiency afforded a significant renal protective effect against IRI in experimental mice, which could be linked with the inflammasome-independent role of NLRP3 in kidney injury ( 61 ). A later study revealed that MAVS was overexpressed in trichloroethylene (TCE)-sensitized positive mouse renal tubular cells and, mtROS inhibitor Mito TEMPO significantly decreased the expression of MAVS and the assembly of the NLRP3 inflammasome, suggesting that MAVS associates with NLRP3 and induces the activation of the NLRP3 inflammasome, finally contributing to tubular reabsorption dysfunction and kidney injury ( 62 ). Pinto et al.…”

Section: Mavs In Akimentioning

confidence: 99%

Mitochondrial antiviral signaling protein: a potential therapeutic target in renal disease

Wu,

Pei,

Long

et al. 2023

Front. Immunol.

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Mitochondrial antiviral signaling protein (MAVS) is a key innate immune adaptor on the outer mitochondrial membrane that acts as a switch in the immune signal transduction response to viral infections. Some studies have reported that MAVS mediates NF-κB and type I interferon signaling during viral infection and is also required for optimal NLRP3 inflammasome activity. Recent studies have reported that MAVS is involved in various cancers, systemic lupus erythematosus, kidney diseases, and cardiovascular diseases. Herein, we summarize the structure, activation, pathophysiological roles, and MAVS-based therapies for renal diseases. This review provides novel insights into MAVS’s role and therapeutic potential in the pathogenesis of renal diseases.

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Effects of mitochondrial reactive oxygen species-induced NLRP3 inflammasome activation on trichloroethylene-mediated kidney immune injury

Cited by 11 publications

References 31 publications

LRRK2 kinase inhibition protects against Parkinson’s disease-associated environmental toxicants

LRRK2 kinase inhibition protects against Parkinson’s disease-associated environmental toxicants

Inflammasome and pyroptosis in autoimmune liver diseases

Mitochondrial antiviral signaling protein: a potential therapeutic target in renal disease

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