Autophagy down regulates pro-inflammatory mediators in BV2 microglial cells and rescues both LPS and alpha-synuclein induced neuronal cell death

Abstract

Autophagy is a fundamental cellular homeostatic mechanism, whereby cells autodigest parts of their cytoplasm for removal or turnover. Neurodegenerative disorders are associated with autophagy dysregulation, and drugs modulating autophagy have been successful in several animal models. Microglial cells are phagocytes in the central nervous system (CNS) that become activated in pathological conditions and determine the fate of other neural cells. Here, we studied the effects of autophagy on the production of pro-inflammatory molecules in microglial cells and their effects on neuronal cells. We observed that both trehalose and rapamycin activate autophagy in BV2 microglial cells and down-regulate the production of pro-inflammatory cytokines and nitric oxide (NO), in response to LPS and alpha-synuclein. Autophagy also modulated the phosphorylation of p38 and ERK1/2 MAPKs in BV2 cells, which was required for NO production. These actions of autophagy modified the impact of microglial activation on neuronal cells, leading to suppression of neurotoxicity. Our results demonstrate a novel role for autophagy in the regulation of microglial cell activation and pro-inflammatory molecule secretion, which may be important for the control of inflammatory responses in the CNS and neurotoxicity.

Microglial glutamate release evoked by α‐synuclein aggregates is prevented by dopamine

“…Note that in some culture settings, toxic effects of aggregated forms of αS have been reported at much lower concentrations (Kim et al, 2013;Zhang et al, 2005). Concentrations comparable to those used by us in the present study were, however, required in other paradigms (Bussi et al, 2017;Hoffmann et al, 2016). We have no definite explanation for such differences, which may be attributable to different culture conditions and various procedures used to generate aggregated species of αS.…”

“…Using a model system of purified microglial cell cultures, we established that amyloid fibrils of αS had the capacity to stimulate FIGURE 5 Dopamine prevents glutamate release induced by αSa in microglial cells through D 1 receptor activation. Concentrations comparable to those used by us in the present study were, however, required in other paradigms (Bussi et al, 2017;Hoffmann et al, 2016). Data are means ± SEM (n = 6).…”

A Novel Quinolyl‐Substituted Analogue of Resveratrol Inhibits LPS‐Induced Inflammatory Responses in Microglial Cells by Blocking the NF‐κB/MAPK Signaling Pathways

“…The inflammatory and neurotoxic mediator NO is released from activated microglia. Excessive release of NO may be involved in contribute to the development of neurodegenerative diseases . NO is synthesized from l ‐arginine by iNOS in microglia .…”

Trehalose as a promising therapeutic candidate for the treatment of Parkinson's disease

“…Interestingly, the disruption of the integrity of the blood-brain barrier and also endothelial cell "cluster" formation, which occur in MPTP-intoxicated mice, were diminished by trehalose through its ability to restore the levels of two tight junctional proteins (ZO-1 and occludin). In a recent study, Bussi et al (2017) showed that exposure to both rapamycin and trehalose efficiently promoted autophagy and decreased the release of proinflammatory mediators, including NO, in response to LPS and αsynuclein in BV2 microglial cells (Table 1). The link between (Table 1; He et al, 2014).…”

“…Moreover, trehalose efficiently attenuated NF-κB activation by down-regulation of toll-like receptor 4 (TLR4) and protected the PD animal model from LPS-mediated neuroinflammation (Minutoli et al, 2008). In a recent study, Bussi et al (2017) showed that exposure to both rapamycin and trehalose efficiently promoted autophagy and decreased the release of proinflammatory mediators, including NO, in response to LPS and αsynuclein in BV2 microglial cells (Table 1). Autophagy may play a critical role in the control of inflammatory responses through inhibition of spurious inflammasome activation and down-regulation of immune response, induced by the activated inflammasome (Lupfer et al, 2013;Nakahira et al, 2011;Saitoh et al, 2008), and inhibition of type I interferon responses either directly or indirectly (Konno, Konno, & Barber, 2013;Liang et al, 2014;Saitoh et al, 2009).…”