Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinson’s disease

Abstract

The NLRP3 inflammasome signaling pathway is a major contributor to the neuroinflammatory process in the central nervous system. Oxidative stress and mitochondrial dysfunction are key pathophysiological processes of many chronic neurodegenerative diseases, including Parkinson’s disease (PD). However, the inter-relationship between mitochondrial defects and neuroinflammation is not well understood. In the present study, we show that impaired mitochondrial function can augment the NLRP3 inflammasome-driven proinflammatory cascade in microglia. Primary mouse microglia treated with the common inflammogen LPS increased NLRP3 and pro-IL-1β expression. Interestingly, exposure of LPS-primed microglial cells to the mitochondrial complex-I inhibitory pesticides rotenone and tebufenpyrad specifically potentiated the NLRP3 induction, ASC speck formation and pro-IL-1β processing to IL-1β in a dose-dependent manner, indicating that mitochondrial impairment heightened the NLRP3 inflammasome-mediated proinflammatory response in microglia. The neurotoxic pesticide-induced NLRP3 inflammasome activation was accompanied by bioenergetic defects and lysosomal dysfunction in microglia. Furthermore, the pesticides enhanced mitochondrial ROS generation in primary microglia, while amelioration of mitochondria-derived ROS by the mitochondria-targeted antioxidant mito-apocynin completely abolished IL-1β release, indicating mitochondrial ROS drives potentiation of the NLRP3 inflammasome in microglia. Exposure to conditioned media obtained from mitochondrial inhibitor-treated, LPS-primed microglial cells, but not unprimed cells, induced dopaminergic neurodegeneration in cultured primary mesencephalic and human dopaminergic neuronal cells (LUHMES). Notably, our in vivo results with chronic rotenone rodent models of PD further support the activation of proinflammatory NLRP3 inflammasome signaling due to mitochondrial dysfunction. Collectively, our results demonstrate that mitochondrial impairment in microglia can amplify NLRP3 inflammasome signaling, which augments the dopaminergic neurodegenerative process.

Inflammasome Activation by Methamphetamine Potentiates Lipopolysaccharide Stimulation of IL-1β Production in Microglia

“…Although our goal is to investigate the role of the inflammasome-mediated proinflammatory signal in Meth-potentiation of HIV-associated neurotoxicity, little is known about HIV-1 protein as the first signal for the inflammasome activation. LPS is typically used as the first priming signal on microglia for inflammasome studies (Halle et al, 2008; Shi et al, 2012; Sarkar et al, 2017). The process of the LPS-primed NLRP3 inflammasome is well characterized and involved with the transcriptional induction (pro-IL-1β and NLRP3 induction) and multiple posttranslational events (extracellular signal regulated kinase 1 phosphorylation, proteasome inhibition, and NLRP3 deubiquitination) (Juliana et al, 2012; Ghonime et al, 2014).…”

“…Previous study reported that Meth induces the release of damage-associated molecular patterns (DAMPs) such as high mobility group box-a (HMGB1) that indirectly targets the microglia to upregulate IL-1β expression (Colton, 2009). In a recent study focusing on inflammasome activation in Parkinson’s disease, the author discovered that after priming with LPS as first signal, the mitochondrial complex-1 inhibiting pesticide rotenone activated the inflammasome-induced IL-1β release and thus, promote the dopaminergic neurotoxicity (Sarkar et al, 2017). IL-1β is a well-recognized cytokine in the orchestration of CNS inflammation and is associated with elevated risk of drug dependence (Liu et al, 2009; Liu et al, 2011).…”

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

“…In addition, human dopaminergic neuronal cells were cultured with conditioned media from LPS‐primed rotenone‐treated primary microglial cells, which caused NLRP3 inflammasome‐mediated dopaminergic neurodegeneration. Similarly, chronic administration of rotenone in a rodent model of PD activated the NLRP3 inflammasome pathway through microglial mitochondrial dysfunction and induced dopaminergic neuronal cell death . The P2X7 receptor, a known mediator of NLRP3 inflammasome activation and release of cytokines, is ubiquitously expressed in microglia .…”

“…Cell death occurs by proteolytic enzyme caspase 1‐mediated activation of IL‐1β, and IL‐18, followed by subsequent formation of membrane pores and cell lysis, a process called pyroptosis . Several individual studies of in vitro and in vivo models of PD have suggested a clear link between aggregation of α‐synuclein, followed by mitochondrial reactive oxygen species (ROS) generation and cathepsin B release with the activation of microglial NLRP3 inflammation‐mediated pyroptotic death of dopaminergic neurons in the SNpc . On the other hand, a rare single‐nucleotide polymorphism (SNP) of NLRP3 has been reported to decrease the risk of developing PD, which proves the authentication of the role of NLRP3 inflammasome in development of PD .…”

SIRT3 activator honokiol ameliorates surgery/anesthesia‐induced cognitive decline in mice through anti‐oxidative stress and anti‐inflammatory in hippocampus

“…Emerging evidence showed that neuroinflammation and oxidative stress are two pivotal roles in pathophysiological process of postoperative cognitive decline and other neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD, and multiple sclerosis (MS) . An accumulating body of studies indicated that using some anti‐inflammatory or antioxidant interventions, such as anti‐TNF antibody, aspirin‐triggered resolvin D1 (AT‐RvD1) or resveratrol, could inhibit the neuroinflammation and oxidative stress in the models of surgical trauma or neurodegenerative diseases .…”