δ-Opioid receptor activation ameliorates lipopolysaccharide-induced inflammation and apoptosis by inhibiting the MAPK/caspase-3 pathway in BV2 microglial cells

Cheng, Min; Geng, Yue; Chen, Yeting; Zhang, Yongjie; Guo, Runjie; Xu, Hong; Liang, Jianfeng; Xie, Jiajun; Zhang, Zean; Tian, Xue

doi:10.1007/s00221-020-05983-9

Cited by 12 publications

(21 citation statements)

References 45 publications

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“…We provided the first evidence in this work that DOR maintained a low density in the BV2 cells, and its expression was closely associated with microglial dynamic polarization. Our data partially support the view of Cheng et al (2021) , who found a colocalization of DOR protein and CD68 + or F4/80 + labeled microglia in human and mouse brain tissues as well as an existence of DOR in BV2 culture cells. However, there is a major difference between our findings and those of Cheng’s in terms of the regulation of DOR expression in LPS-treated BV2 cells.…”

Section: Discussionsupporting

confidence: 91%

“…Our results were based on the simultaneous comparison among LPS, IL4 and hypoxia groups and the consistency of both immunofluorescent and Western blot data. The reasons behind the difference between our observations and those of Cheng et al (2021) are very likely related to the differences in the concentrations of LPS and the exposure durations between our and their experiments because DOR expression is sensitive to various stresses and differs in different conditions ( Ma et al, 2005 ; Popiolek-Barczyk and Mika, 2016 ; Zhu et al, 2018 ; Polo et al, 2019 ; Xu et al, 2019 ).…”

Section: Discussioncontrasting

confidence: 78%

“…We have made following interesting findings in the BV2 cell, an immortalized murine microglia model ( Khan and Langmann, 2020 ; Wu et al, 2020 ; Cheng et al, 2021 ): (1) DOR maintained a low density in resting microglia and could be largely upregulated by IL4 and hypoxia; (2) DOR activation with specific DOR agonist UFP-512 significantly suppressed BV2 inflammatory transformations under LPS injury and hypoxic injury with high concentrations of UFP-512 being effective to inhibit the M2 transformations of microglia under IL4 condition; (3) DOR antagonism, naltrindole, enhanced both microglial M1 and M2 activation in LPS and hypoxic conditions; (4) DOR activation inhibited the production of inflammatory cytokines and iNOS under LPS injury and hypoxic injury, while reduced the secretion of anti-inflammatory cytokines under IL4 condition; (5) Knocking down DOR promoted microglia activation and inflammatory events, while overexpressing DOR induced an opposite effect; and (6) DOR-mediated protection on PC12 cells was enhanced by co-culturing with the conditioned medium from DOR agonist-treated BV2 cells under LPS insult or hypoxic stress.…”

Section: Discussionmentioning

confidence: 99%

“… Shrivastava et al (2017) reported that μ-opioid receptor and DOR differentially regulate microglial inflammation in response to neonatal ethanol in the hypothalamus of rats, and they found that DOR activation promoted microglial secretion of anti-inflammatory cytokines and suppressed ethanol induced microglial inflammatory activation. More recently, a research group examined the role of DOR in lipopolysaccharide (LPS)-induced microglial activation, they observed that DOR activation could inhibit LPS-induced inflammatory response and improved microglia survival by switching microglia to a beneficial phenotype ( Cheng et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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A Critical Role of δ-Opioid Receptor in Anti-microglial Activation Under Stress

Zhi

Peng

et al. 2022

Front. Aging Neurosci.

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Microglia are involved in the regulation of cerebral homeostasis and pathogen confrontation. There is, however, evidence showing that excessive microglia activation is implicated in various age-related cerebral diseases. On the other hand, microglia may experience complex changes of polarization in pathological insults, i.e., from a proinflammatory M1 to an anti-inflammatory M2 phenotype, which differentially contribute to the exacerbation or alleviation of cellular injury. Remolding the phenotype of microglia or inhibiting the excessive activation of microglia seems to be a promising approach against neurodegenerative pathologies. Since δ-opioid receptor (DOR) activation exhibits a strong protective capacity against various neuronal injuries, especially the hypoxic/ischemic injury, we asked if the DOR-induced neuroprotection is associated with its effect on microglia. We explored this fundamental issue by using pharmacological and genetic approaches in the BV2 cell line, a general type of microglial cells. The results showed that DOR expression significantly increased in the activated microglial M2 phenotype, but slightly decreased in the microglial M1 phenotype. Hypoxia induced dual polarizations of BV2 cells with an increase in DOR expression. Administration of a specific DOR agonist, UFP-512, largely inhibited lipopolysaccharide (LPS) or hypoxia-induced microglial M1 activation and inflammatory activity with high concentrations of UFP-512 being effective to reverse the interleukin-4 (IL4)-induced microglial activation. Consistent with these observations, inhibiting DOR or knocking-down DOR promoted the excessive activation of BV2 cells in both M1 and M2 directions, while DOR overexpression did the opposite. Furthermore, the PC12 cells exposed to the conditioned medium of BV2 cells treated by UFP-512 grew better than those treated directly with UFP-512 under LPS or hypoxic insults. DOR inhibitor naltrindole could block all the effects of DOR activation. The medium from the BV2 cells with DOR knock-down decreased the viability of PC12 cell, while the medium from the BV2 cells with DOR overexpression largely attenuated LPS or hypoxic injury in the PC12 cells. These first data suggest a close linkage between DOR expression/function and microglial polarization and a critical role of DOR in negative controlling microglial activation. Our work provides a novel clue for new protective strategies against neurodegenerative pathophysiology through DOR-mediated regulation of microglia.

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Section: Discussionsupporting

confidence: 91%

Section: Discussioncontrasting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Critical Role of δ-Opioid Receptor in Anti-microglial Activation Under Stress

Zhi

Peng

et al. 2022

Front. Aging Neurosci.

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“…Those cells constantly survey the brain milieu and in response to altered microenvironment homeostasis, microglia cells become reactive and can shift their morphology, which facilitates migration to the injury site ( Thameem Dheen et al, 2007 ; Griffiths et al, 2009 ). Marked and disseminated microglial reaction may result and perpetuate the neuroinflammatory state, also contributing to the neurodegeneration through the release of free radicals, excessive nitric oxide (NO), inducible nitric oxide synthase (iNOS), and multiple chemokines and cytokines, such as IL-1β, IL-6, IL-8, IL-12, IL-15, IL-10, and TNF-α ( Shinozaki et al, 2019 ; Cheng et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Necrotic-like BV-2 microglial cell death due to methylmercury exposure

Martins

Novo²,

Fonseca³

et al. 2022

Front. Pharmacol.

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Methylmercury (MeHg) is a dangerous environmental contaminant with strong bioaccumulation in the food chain and neurotoxic properties. In the nervous system, MeHg may cause neurodevelopment impairment and potentially interfere with immune response, compromising proper control of neuroinflammation and aggravating neurodegeneration. Human populations are exposed to environmental contamination with MeHg, especially in areas with strong mining or industrial activity, raising public health concerns. Taking this into consideration, this work aims to clarify pathways leading to acute toxic effects caused by MeHg exposure in microglial cells. BV-2 mouse microglial cells were incubated with MeHg at different concentrations (0.01, 0.1, 1 and 10 µM) for 1 h prior to continuous Lipopolysaccharide (LPS, 0.5 μg/ml) exposure for 6 or 24 h. After cell exposure, reactive oxygen species (ROS), IL-6 and TNF-α cytokines production, inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO) release, metabolic activity, propidium iodide (PI) uptake, caspase-3 and -9 activities and phagocytic activity were assessed. MeHg 10 µM decreased ROS formation, the production and secretion of pro-inflammatory cytokines IL-6, TNF-α, iNOS immunoreactivity, the release of NO in BV-2 cells. Furthermore, MeHg 10 µM decreased the metabolic activity of BV-2 and increased the number of PI-positive cells (necrotic-like cell death) when compared to the respective control group. Besides, MeHg did not interfere with caspase activity or the phagocytic profile of cells. The short-term effects of a high concentration of MeHg on BV-2 microglial cells lead to impaired production of several pro-inflammatory mediators, as well as a higher microglial cell death via necrosis, compromising their neuroinflammatory response. Clarifying the mechanisms underlying MeHg-induced neurotoxicity and neurodegeneration in brain cells is relevant to better understand acute and long-term chronic neuroinflammatory responses following MeHg exposure.

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