Caffeine Inhibits Activation of the NLRP3 Inflammasome via Autophagy to Attenuate Microglia-Mediated Neuroinflammation in Experimental Autoimmune Encephalomyelitis

Wang, Huiqi; Song, Kai-Yi; Feng, Jinzhou; Huang, Siyuan; Guo, Xiufang; Zhang, Lei; Zhang, Gang; Huo, Yingchao; Zhang, Rongrong; Ma, Yue; Hu, Qingzhe; Qin, Xinyue

doi:10.1007/s12031-021-01894-8

Cited by 22 publications

(11 citation statements)

References 72 publications

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“…IF analysis results showed increased colocalization of inflammasome-associated proteins, namely, NLRP3 and caspase 1, suggesting that they interacted to form the active NLRP3 inflammasome complex. The present study is the first to report that caffeine prevents the activation of the NLRP3 inflammasome and the increases in NLRP3, ASC, caspase 1, and IL-1β protein levels, which are consistent with results obtained from in vitro models [ 40 , 41 ], a model of lung damage [ 42 ], and experimental models of neuroinflammation [ 43 , 44 ]. NLRP3 inflammasome is most prominently expressed in Kupffer cells and liver sinusoidal endothelial cells and moderately expressed in periportal myofibroblasts, hepatic stellate cells, and hepatocytes [ 10 , 45 ]; therefore, caffeine NLRP3 inhibition may principally occur in Kupffer cells.…”

Section: Discussionsupporting

confidence: 91%

Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model

Vargas-Pozada

Ramos‐Tovar²,

Rodríguez-Callejas

et al. 2022

IJMS

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Caffeine elicits protective effects against liver diseases, such as NASH; however, its mechanism of action involving the pyrin domain-containing-3 (NLRP3) inflammasome signaling pathway remains to be elucidated. This study aimed to evaluate the effect of caffeine on the NLRP3 inflammasome signaling pathway in a rat model of NASH. NASH was induced by feeding rats a high-fat, -sucrose, and -cholesterol diet (HFSCD) for 15 weeks along with a weekly low dose (400 mg/kg, i.p.) of CCl4. Caffeine was administered at 50 mg/kg p.o. The effects of HFSCD+CCl4 and caffeine on the liver were evaluated using biochemical, ultrastructural, histological, and molecular biological approaches. The HFSCD+CCl4-treated rats showed fat accumulation in the liver, elevated levels of inflammatory mediators, NLRP3 inflammasome activation, antioxidant dysregulation, and liver fibrosis. Caffeine reduced necrosis, cholestasis, oxidative stress, and fibrosis. Caffeine exhibited anti-inflammatory effects by attenuating NLRP3 inflammasome activation. Moreover, caffeine prevented increases in toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) protein levels and mitigated the phosphorylation of mitogen-activated protein kinase (MAPK). Importantly, caffeine prevented the activation of hepatic stellate cells. This study is the first to report that caffeine ameliorates NASH by inhibiting NLRP3 inflammasome activation through the suppression of the TLR4/MAPK/NF-κB signaling pathway.

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Section: Discussionsupporting

confidence: 91%

Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model

Vargas-Pozada

Ramos‐Tovar²,

Rodríguez-Callejas

et al. 2022

IJMS

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“…It is evidenced that NLRP3 inflammasome expression in microglia, astrocytes, and brain microvessels endothelial cells which activation may create conditions necessary for active IL-1β synthesis [47][48][49]. The in vivo study on C57BL/6 mice reported that CAF may reduce NLRP3 inflammasome activation via the induction of autophagy in microglial cells [50]. Considering this, similar action of CAF on NLRP3 inflammasome in the ovine hypothalamus (including also brain microvessels) may be expected.…”

Section: Discussionmentioning

confidence: 87%

Acute Effect of Caffeine on the Synthesis of Pro-Inflammatory Cytokines in the Hypothalamus and Choroid Plexus during Endotoxin-Induced Inflammation in a Female Sheep Model

Szczepkowska

Wójcik

Tomaszewska-Zaremba

et al. 2021

IJMS

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This study was designed to determine the effect of acute caffeine (CAF) administration, which exerts a broad spectrum of anti-inflammatory activity, on the synthesis of pro-inflammatory cytokines and their receptors in the hypothalamus and choroid plexus (ChP) during acute inflammation caused by the injection of bacterial endotoxin—lipopolysaccharide (LPS). The experiment was performed on 24 female sheep randomly divided into four groups: control; LPS treated (iv.; 400 ng/kg of body mass (bm.)); CAF treated (iv.; 30 mg/kg of bm.); and LPS and CAF treated. The animals were euthanized 3 h after the treatment. It was found that acute administration of CAF suppressed the synthesis of interleukin (IL-1β) and tumor necrosis factor (TNF)α, but did not influence IL-6, in the hypothalamus during LPS-induced inflammation. The injection of CAF reduced the LPS-induced expression of TNF mRNA in the ChP. CAF lowered the gene expression of IL-6 cytokine family signal transducer (IL6ST) and TNF receptor superfamily member 1A (TNFRSF1) in the hypothalamus and IL-1 type II receptor (IL1R2) in the ChP. Our study on the sheep model suggests that CAF may attenuate the inflammatory response at the hypothalamic level and partly influence the inflammatory signal generated by the ChP cells. This suggests the potential of CAF to suppress neuroinflammatory processes induced by peripheral immune/inflammatory challenges.

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“…IL-1β) in macrophages and primary microglia [232][233][234][235]. Notably, in preclinical models of hypoxic-ischemia and autoimmune encephalomyelitis, caffeine inhibited NLRP3 inflammasome activation and microglial activation to confer neuroprotection and attenuate disease pathology [236,237]. Therefore, in addition to modulating neuronal signalling, targeting A 2A R on microglia may present an opportunity to target neuroinflammation associated with AD.…”

Section: The Role Of a 1 R And A 2a R In Dementiamentioning

confidence: 99%

Adenosine receptor signalling in Alzheimer’s disease

Trinh

Baltos

Hellyer

et al. 2022

Purinergic Signalling

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Alzheimer’s disease (AD) is the most common dementia in the elderly and its increasing prevalence presents treatment challenges. Despite a better understanding of the disease, the current mainstay of treatment cannot modify pathogenesis or effectively address the associated cognitive and memory deficits. Emerging evidence suggests adenosine G protein-coupled receptors (GPCRs) are promising therapeutic targets for Alzheimer’s disease. The adenosine A1 and A2A receptors are expressed in the human brain and have a proposed involvement in the pathogenesis of dementia. Targeting these receptors preclinically can mitigate pathogenic β-amyloid and tau neurotoxicity whilst improving cognition and memory. In this review, we provide an accessible summary of the literature on Alzheimer’s disease and the therapeutic potential of A1 and A2A receptors. Although there are no available medicines targeting these receptors approved for treating dementia, we provide insights into some novel strategies, including allosterism and the targeting of oligomers, which may increase drug discovery success and enhance the therapeutic response.

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Caffeine Inhibits Activation of the NLRP3 Inflammasome via Autophagy to Attenuate Microglia-Mediated Neuroinflammation in Experimental Autoimmune Encephalomyelitis

Cited by 22 publications

References 72 publications

Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model

Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model

Acute Effect of Caffeine on the Synthesis of Pro-Inflammatory Cytokines in the Hypothalamus and Choroid Plexus during Endotoxin-Induced Inflammation in a Female Sheep Model

Adenosine receptor signalling in Alzheimer’s disease

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