Rotenone-induced Impairment of Mitochondrial Electron Transport Chain Confers a Selective Priming Signal for NLRP3 Inflammasome Activation

Won, Ji-Hee; Park, Sangjun; Hong, Sujeong; Son, Seunghwan; Yu, Je-Wook

doi:10.1074/jbc.m115.667063

Cited by 104 publications

(90 citation statements)

References 35 publications

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“…Accordingly, in the present study ROT-induced mitochondrial electron transport chain (ETC) complex I inhibition and subsequent generation of ROS might have contributed to the excessive ROS generation in the presence of LPS. Consistent with our data, in a recent study ROT was found to induce NLRP3 inflammasome activation in the presence of an inflammasome activator (ATP) via a mechanism involving the generation of high grade mitochondrial ROS (Won et al, 2015). In another study, the saturated fatty acid palmitate was found to induce NLRP3 inflammasome activation and the release of IL-1β via a mitochondrial ROS-mediated mechanism (Wen et al, 2011a).…”

Section: Discussionsupporting

confidence: 92%

“…Treatment of murine macrophages with ROT leads to NLRP3 activation and IL-1β release in a delayed fashion although only in the presence of an inflammasome activator ATP (Won et al, 2015). Mitochondria targeted toxins have been shown to influence cell viability (Ferger et al, 2010), in order to rule out toxic effects of ROT on our experimental end points first we determined the effects of ROT and LPS on cell viability using the MTS assay, which measures mitochondrial dehydrogenase activity.…”

Section: Resultsmentioning

confidence: 99%

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Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System

Lawana

Singh

Sarkar

et al. 2017

J Neuroimmune Pharmacol

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A growing body of evidence suggests that excessive microglial activation and pesticide exposure may be linked to the etiology of PD; however, the mechanisms involved remain elusive. Emerging evidence indicates that intracellular inflammasome complex namely NLRP3 complex is involved in the recognition and execution of host inflammatory response. Thus, in the present study, we investigated the hypothesis that NLRP3 inflammasome activation is linked to rotenone (ROT)-induced microglial activation which is dependent upon a priming stimulus by a pathogen-associated molecular pattern (PAMP) or damage associated molecular pattern (DAMP), respectively. Herein using both BV2 cells and primary microglial cells, we show that LPS priming and subsequent ROT stimulation enhanced NLRP3 inflammasome activation, c-Abl and PKCδ activation, mitochondrial dysfunction, NF-κB activation, and autophagic markers, while TFEB levels were decreased dramatically. Mechanistic studies revealed c-Abl acts as a proximal signal that exacerbated the activation of the afore mentioned markers. Intriguingly, siRNA-mediated depletion or pharmacological inhibition of c-Abl via dasatinib abrogated LPS and ROT-induced microglial activation response via attenuation of NLRP3 inflammasome activation, mitochondrial oxidative stress, and ALS dysfunction. Moreover, mitoTEMPO, a mitochondrial antioxidant, attenuated NLRP3 inflammasome activation effects via blockade of c-Abl and PKCδ activation. In LPS treated mice, dasatinib attenuated NLRP3 inflammasome activation, c-Abl and PKCδ activation; and sickness behavior. Together our findings identify an exaggerated ROS/c-Abl/NLRP3 signaling axis in the heightened microglial activation response evidenced in LPS-primed ROT-stimulated microglial cells and suggest that targeting c-Abl-regulated NLRP3 inflammasome signaling offers a novel therapeutic strategy for PD treatment.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System

Lawana

Singh

Sarkar

et al. 2017

J Neuroimmune Pharmacol

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“…5d, upper panel). To provide more evidence that 25-HC could impair the function of mitochondria, we determined another indication of mitochondrial damage by co-staining with MitoTracker Green and MitoTracker Deep Red to measure the dissipation of mitochondrial membrane potential333435. Consistent with mtROS production, treatment with 25-HC caused an obvious increase in the damaged mitochondria-containing cell population (Fig.…”

Section: Resultsmentioning

confidence: 98%

25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome

et al. 2016

Self Cite

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X-linked adrenoleukodystrophy (X-ALD), caused by an ABCD1 mutation, is a progressive neurodegenerative disorder associated with the accumulation of very long-chain fatty acids (VLCFA). Cerebral inflammatory demyelination is the major feature of childhood cerebral ALD (CCALD), the most severe form of ALD, but its underlying mechanism remains poorly understood. Here, we identify the aberrant production of cholesterol 25-hydroxylase (CH25H) and 25-hydroxycholesterol (25-HC) in the cellular context of CCALD based on the analysis of ALD patient-derived induced pluripotent stem cells and ex vivo fibroblasts. Intriguingly, 25-HC, but not VLCFA, promotes robust NLRP3 inflammasome assembly and activation via potassium efflux-, mitochondrial reactive oxygen species (ROS)- and liver X receptor (LXR)-mediated pathways. Furthermore, stereotaxic injection of 25-HC into the corpus callosum of mouse brains induces microglial recruitment, interleukin-1β production, and oligodendrocyte cell death in an NLRP3 inflammasome-dependent manner. Collectively, our results indicate that 25-HC mediates the neuroinflammation of X-ALD via activation of the NLRP3 inflammasome.

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“…Interestingly, mitochondria do play a role during the formation of inflammasome. NOD-like receptor containing pyrin domain 3 (NLRP3) inflammasome assembly requires mitochondrial ROS generation [175] and is associated with concurrent mitochondrial depolarization and mtDNA release [176]. It has also been suggested that autophagy/mitophagy inhibition could promote NLRP3 inflammasome activation by inducing mitochondrial dysfunction, which, in turn, increases again ROS production [175] and promoting cardiolipin accumulation on OMM, another signal triggering NLRP3 inflammasome assembly [177].…”

Section: Inflammationmentioning

confidence: 99%

The mitochondrial dynamics in cancer and immune-surveillance

Simula

Nazio

Campello

2017

Seminars in Cancer Biology

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A B S T R A C TMitochondria-shaping proteins control the dynamic equilibrium between fusion and fission of the mitochondrial network. Their balance is strictly required to regulate various processes, including the quality of mitochondria, cell metabolism, cell death, proliferation and cell migration. Alterations in these processes are frequently encountered in cancer, during both its onset and later progression, as evidence emerge connecting alterations in mitochondrial dynamics with cancer development. In recent years, novel therapeutic approaches to fight against different human tumors aim at exploiting the immune system's ability to specifically recognize tumor antigens, thus killing malignant cells in a process named immune-surveillance. Interestingly, data are accumulating on the role that mitochondrial dynamics play also for the correct function of both the innate and the adaptive immune system. By this review, we overview how mitochondrial dynamics can affect various processes during cancer development, acting directly on tumor cells or indirectly on cells responsible for tumor aggression and defence.

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Rotenone-induced Impairment of Mitochondrial Electron Transport Chain Confers a Selective Priming Signal for NLRP3 Inflammasome Activation

Cited by 104 publications

References 35 publications

Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System

Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System

25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome

The mitochondrial dynamics in cancer and immune-surveillance

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