Manganese induces neuroinflammation via NF-κB/ROS NLRP3 pathway in rat brain striatum and HAPI cells

Zhao, Xinyuan; Yin, Lifeng; Wu, Yifan; Han, Muxi; Yin, Zhimin; Cong, Yewen; Liu, Yiming; Chen, Gang; Jiang, Junkang

doi:10.1007/s13273-019-0021-0

Cited by 8 publications

(10 citation statements)

References 35 publications

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“…Particularly, Mn exposure in rats (2, 5, 10 mg/kg MnCl 2 i.g. for 30 days) resulted in striatal NF-κB activation leading to the formation of NLRP3 inflammasome complex and the consequent ROS-mediated activation with subsequent IL-1β and IL-18 secretion by microglia [ 86 ]. Mn-induced activation of NLRP3-CASP1 (caspase 1) inflammasome pathway in Mn-exposed rats (100 mg/kg Mn s.c. 3 times a week) and BV2 cells (100 μM Mn for 6 h) may also be associated with autophagy-lysosomal dysfunction, whereas release of lysosomal CTSB (cathepsin B) plays a significant role in Mn-induced NLRP3-CASP1 inflammasome activation [ 87 ].…”

Section: Mn-induced Alterations In Subcellular and Multicellular Biologymentioning

confidence: 99%

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

Tinkov

Paoliello

Mazilina

et al. 2021

IJMS

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Understanding of the immediate mechanisms of Mn-induced neurotoxicity is rapidly evolving. We seek to provide a summary of recent findings in the field, with an emphasis to clarify existing gaps and future research directions. We provide, here, a brief review of pertinent discoveries related to Mn-induced neurotoxicity research from the last five years. Significant progress was achieved in understanding the role of Mn transporters, such as SLC39A14, SLC39A8, and SLC30A10, in the regulation of systemic and brain manganese handling. Genetic analysis identified multiple metabolic pathways that could be considered as Mn neurotoxicity targets, including oxidative stress, endoplasmic reticulum stress, apoptosis, neuroinflammation, cell signaling pathways, and interference with neurotransmitter metabolism, to name a few. Recent findings have also demonstrated the impact of Mn exposure on transcriptional regulation of these pathways. There is a significant role of autophagy as a protective mechanism against cytotoxic Mn neurotoxicity, yet also a role for Mn to induce autophagic flux itself and autophagic dysfunction under conditions of decreased Mn bioavailability. This ambivalent role may be at the crossroad of mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis. Yet very recent evidence suggests Mn can have toxic impacts below the no observed adverse effect of Mn-induced mitochondrial dysfunction. The impact of Mn exposure on supramolecular complexes SNARE and NLRP3 inflammasome greatly contributes to Mn-induced synaptic dysfunction and neuroinflammation, respectively. The aforementioned effects might be at least partially mediated by the impact of Mn on α-synuclein accumulation. In addition to Mn-induced synaptic dysfunction, impaired neurotransmission is shown to be mediated by the effects of Mn on neurotransmitter systems and their complex interplay. Although multiple novel mechanisms have been highlighted, additional studies are required to identify the critical targets of Mn-induced neurotoxicity.

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Section: Mn-induced Alterations In Subcellular and Multicellular Biologymentioning

confidence: 99%

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

Tinkov

Paoliello

Mazilina

et al. 2021

IJMS

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“…This activation led to the induction of the multiprotein NLRP3 inflammasome complex to promote neuroinflammation. Zhao et al showed that Mn exposure facilitated the activation of NLRP3 inflammasome to promote the production of IL-1β and IL-18 in dose- and time-dependent manners in HAPI cells [ 39 ]. Data from the current study demonstrated that there was an increase in the expression of the NLRP3 gene and protein expression.…”

Section: Resultsmentioning

confidence: 99%

Blockage of KHSRP-NLRP3 by MCC950 Can Reverse the Effect of Manganese-Induced Neuroinflammation in N2a Cells and Rat Brain

Singh

Shaikh

et al. 2022

IJMS

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Manganese neurotoxicity has been reported to cause a neurodegenerative disease known as parkinsonism. Previous reports have shown that the expression of the KH-type splicing regulatory protein (KHSRP), a nucleic acid-binding protein, and NLRP3 is increased upon Mn exposure. However, the relation between these two during Mn toxicity has not been fully deduced. The mouse neuroblastoma (N2a) and SD rats are treated with LPS and MnCl2 to evaluate the expression of KHSRP and NLRP3. Further, the effect of the NLRP3 inhibitor MCC950 is checked on the expression of NLRP3, KHSRP and pro-inflammatory markers (TNFα, IL-18 and IL-1β) as well as the caspase-1 enzyme. Our results demonstrated an increment in NLRP3 and KHSRP expression post-MnCl2 exposure in N2a cells and rat brain, while on the other hand with LPS exposure only NLRP3 expression levels were elevated and KHSRP was found to be unaffected. An increased expression of KHSRP, NLRP3, pro-inflammatory markers and the caspase-1 enzyme was observed to be inhibited with MCC950 treatment in MnCl2-exposed cells and rats. Manganese exposure induces NLRP3 and KHSRP expression to induce neuroinflammation, suggesting a correlation between both which functions in toxicity-related pathways. Furthermore, MCC950 treatment reversed the role of KHSRP from anti-inflammatory to pro-inflammatory.

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“…Mn exposure has previously associated with pathologic changes in the several brain regions; the striatum is particularly susceptible to the deleterious effect of Mn. 54 Similarly, Mn accumulates in the hippocampus, cerebellum, 55,56 and cortex. 57,58 Although it well established that Mn deposition in the brain is region-specific owing to differential expression of important Mn transporters-DMT-1, transferrin, across specific brain regions, 59 sex-specific distribution and metabolism of Mn have also been recorded both in humans [60][61][62] and experimental models.…”

Section: Discussionmentioning

confidence: 99%

“…We also examined potential sex‐influenced variations in Mn deposition across different brain regions ‐ striatum, cortex, hippocampus, and cerebellum, following Mn exposure. Mn exposure has previously associated with pathologic changes in the several brain regions; the striatum is particularly susceptible to the deleterious effect of Mn 54 . Similarly, Mn accumulates in the hippocampus, cerebellum, 55,56 and cortex 57,58 .…”

Section: Discussionmentioning

confidence: 99%

Sex‐dependent metal accumulation and immunoexpression of Hsp70 and Nrf2 in rats' brain following manganese exposure

Ijomone

Iroegbu

Morcillo

et al. 2022

Environmental Toxicology

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Manganese (Mn), although important for multiple cellular processes, has posed environmental health concerns due to its neurotoxic effects. In recent years, there have been extensive studies on the mechanism of Mn‐induced neuropathology, as well as the sex‐dependent vulnerability to its neurotoxic effects. Nonetheless, cellular mechanisms influenced by sex differences in susceptibility to Mn have yet to be adequately characterized. Since oxidative stress is a key mechanism of Mn neurotoxicity, here, we have probed Hsp70 and Nrf2 proteins to investigate the sex‐dependent changes following exposure to Mn. Male and female rats were administered intraperitoneal injections of MnCl2 (10 mg/kg and 25 mg/kg) 48 hourly for a total of eight injections (15 days). We evaluated changes in body weight, as well as Mn accumulation, Nrf2 and Hsp70 expression across four brain regions; striatum, cortex, hippocampus and cerebellum in both sexes. Our results showed sex‐specific changes in body‐weight, specifically in males but not in females. Additionally, we noted sex‐dependent accumulation of Mn in the brain, as well as in expression levels of Nrf2 and Hsp70 proteins. These findings revealed sex‐dependent susceptibility to Mn‐induced neurotoxicity corresponding to differential Mn accumulation, and expression of Hsp70 and Nrf2 across several brain regions.

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Manganese induces neuroinflammation via NF-κB/ROS NLRP3 pathway in rat brain striatum and HAPI cells

Cited by 8 publications

References 35 publications

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

Blockage of KHSRP-NLRP3 by MCC950 Can Reverse the Effect of Manganese-Induced Neuroinflammation in N2a Cells and Rat Brain

Sex‐dependent metal accumulation and immunoexpression of Hsp70 and Nrf2 in rats' brain following manganese exposure

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