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Mefloquine targets NLRP3 to reduce lipopolysaccharide-induced systemic inflammation and neural injury.

ABSTRACT: The NLR family pyrin domain containing 3 (NLRP3) inflammasome plays an important role in the pathogenesis of a wide variety of human diseases. So far, drugs directly and specifically targeting the NLRP3 inflammasome are not available for clinical use since the safety and efficacy of new compounds are often unclear. A promising approach is thus to identify NLRP3 inhibitors from existing drugs that are already in clinical use. Here, we show that mefloquine, a well-known antimalarial drug, is a highly selective and potent NLRP3 inhibitor by screening a FDA-approved drug library. Mechanistically, mefloquine directly binds to the NLRP3 NACHT and LRR domains to prevent NLRP3 inflammasome activation. More importantly, mefloquine treatment attenuates the symptoms of lipopolysaccharide-induced systemic inflammation and Parkinson's disease-like neural damage in mice. Our findings identify mefloquine as a potential therapeutic agent for NLRP3-driven diseases and migth expand its clinical use considerably.

SUBMITTER: Jiang SY

PROVIDER: S-EPMC10561175 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Mefloquine targets NLRP3 to reduce lipopolysaccharide-induced systemic inflammation and neural injury.

Jiang Si-Yuan SY Tian Tian T Li Wen-Jie WJ Liu Ting T Wang Cong C Hu Gang G Du Ren-Hong RH Liu Yang Y Lu Ming M

EMBO reports 20230825 10

The NLR family pyrin domain containing 3 (NLRP3) inflammasome plays an important role in the pathogenesis of a wide variety of human diseases. So far, drugs directly and specifically targeting the NLRP3 inflammasome are not available for clinical use since the safety and efficacy of new compounds are often unclear. A promising approach is thus to identify NLRP3 inhibitors from existing drugs that are already in clinical use. Here, we show that mefloquine, a well-known antimalarial drug, is a hig ...[more]

PMID: 37621232

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Project description:Retinal neurodegenerative diseases involve a scenario of inflammation and cell death that leads to morphological alterations and visual impairment. Non-ocular inflammatory processes could affect neurodegenerative retinal disorders and their progression, at least in part by activating microglial cells and releasing pro-inflammatory cytokines. Our purpose was to study the consequences of a systemic inflammatory process in the progression of retinal degeneration in P23H rats, a retinitis pigmentosa (RP) model. In order to induce a mild chronic systemic inflammation, we administered low doses of lipopolysaccharide (LPS) from age P20 to P60 to dystrophic P23H rats and healthy SD rats. Visual responsiveness was assessed by electroretinography (ERG). The morphological state of the retinas was analyzed by fluorescent immunohistochemistry (IHC), evaluating the number, morphology, and connectivity of different neuronal populations by means of cell type-specific markers. Microglia density, distribution, and degree of activation were evaluated by IHC and flow cytometry. The expression levels of inflammation- and apoptosis-related genes were analyzed by qRT-PCR arrays. Low-dose LPS administration did not induce significant functional or morphological changes in the retina of SD rats, although at the molecular level, we detected expression changes in genes related to apoptosis. Otherwise, systemic injection of LPS into P23H rats induced a further deterioration in the ERG response, with greater loss of photoreceptors and worsening of synaptic connectivity, accompanied by increasing numbers of microglial cells, which also showed a more intense activation state. Several inflammation- and apoptosis-related genes were upregulated. Our results indicate that chronic exacerbation of the inflammatory response in response to LPS accelerates neurodegeneration in dystrophic P23H rats, suggesting that in patients with ocular neurodegenerative diseases, peripheral damage, as a systemic infection or chronic inflammatory process, could accelerate disease progression, and should be taken into account in order to select an appropriate therapy to revert, block or slow-down the degenerative process.

Project description:BackgroundNovel preventive therapies are needed for postoperative delirium, which especially affects older patients. A mouse model is presented that captures inflammation-associated cortical slow wave activity (SWA) observed in patients, allowing exploration of the mechanistic role of prostaglandin-adenosine signalling.MethodsEEG and cortical cytokine measurements (interleukin 6, monocyte chemoattractant protein-1) were obtained from adult and aged mice. Behaviour, SWA, and functional connectivity were assayed before and after systemic administration of lipopolysaccharide (LPS)+piroxicam (cyclooxygenase inhibitor) or LPS+caffeine (adenosine receptor antagonist). To avoid the confounder of inflammation-driven changes in movement which alter SWA and connectivity, electrophysiological recordings were classified as occurring during quiescence or movement, and propensity score matching was used to match distributions of movement magnitude between baseline and post-LPS administration.ResultsLPS produces increases in cortical cytokines and behavioural quiescence. In movement-matched data, LPS produces increases in SWA (likelihood-ratio test: χ2(4)=21.51, P<0.001), but not connectivity (χ2(4)=6.39, P=0.17). Increases in SWA associate with interleukin 6 (P<0.001) and monocyte chemoattractant protein-1 (P=0.001) and are suppressed by piroxicam (P<0.001) and caffeine (P=0.046). Aged animals compared with adult animals show similar LPS-induced SWA during movement, but exaggerated cytokine response and increased SWA during quiescence.ConclusionsCytokine-SWA correlations during wakefulness are consistent with observations in patients with delirium. Absence of connectivity effects after accounting for movement changes suggests decreased connectivity in patients is a biomarker of hypoactivity. Exaggerated effects in quiescent aged animals are consistent with increased hypoactive delirium in older patients. Prostaglandin-adenosine signalling may link inflammation to neural changes and hence delirium.

Project description:The role of NOD-like receptor protein 3 (NLRP3)-mediated pyroptosis in acute lung injury (ALI) has been well identified previously. Stimulator of interferon genes (STING) is an indispensable adaptor protein, which could regulate inflammation and pyroptosis during infection; however, its role in lipopolysaccharide (LPS)-induced ALI remains obscure. This study aimed to explore whether STING participated in the development of LPS-induced ALI as well as the underlying mechanism. We confirmed that LPS significantly enhanced the expression and phosphorylation of STING in lung tissue and primary macrophages from mice. STING deficiency relieved inflammation and oxidative stress in LPS-treated murine lungs and macrophages. Meanwhile, STING deficiency also abolished the activation of NLRP3 inflammasome and pyroptosis; however, NLRP3 overexpression by adenovirus offset the beneficial effects of STING deficiency in macrophages treated with LPS. Additionally, the level of mitochondrial DNA (mt-DNA) significantly increased in macrophages after LPS treatment. Intriguingly, although exogenous mt-DNA stimulation did not influence the level of STING, it could still trigger the phosphorylation of STING as well as pyroptosis, inflammation, and oxidative stress of macrophages. And the adverse effects induced by mt-DNA could be offset after STING was knocked out. Furthermore, the inhibition of the sensory receptor of cytosolic DNA (cyclic GMP-AMP synthase, cGAS) also blocked the activation of STING and NLRP3 inflammasome, meanwhile, it alleviated ALI without affecting the expression of STING after LPS challenge. Furthermore, cGAS inhibition also blocked the production of cGAMP induced by LPS, indicating that mt-DNA and cGAS could activate STING-NLRP3-mediated pyroptosis independent of the expression of STING. Finally, we found that LPS upregulated the expression of transcription factor c-Myc, which subsequently enhanced the activity of STING promoter and promoted its expression without affecting its phosphorylation. Collectively, our study disclosed that LPS could activate STING in a cytosolic DNA-dependent manner and upregulate the expression of STING in a c-Myc-dependent manner, which cooperatively contribute to ALI.

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Mefloquine targets NLRP3 to reduce lipopolysaccharide-induced systemic inflammation and neural injury.

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Mefloquine targets NLRP3 to reduce lipopolysaccharide-induced systemic inflammation and neural injury.

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