The role of autophagy in modulation of neuroinflammation in microglia

Su, Peng; Zhang, J.; Wang, D.; Zhao, Fang; Cao, Zhi; Aschner, Michael; Luo, Wenjing

doi:10.1016/j.neuroscience.2016.01.035

Cited by 153 publications

(120 citation statements)

References 114 publications

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“…Recently, it was reported that autophagy might influence inflammation and activation of microglia, as well as inflammation might promote or inhibit the process of autophagy [52]. In this context, our work has demonstrated that clemastine can activate autophagy in SOD1-G93A primary microglia, by increasing LC3-II and decreasing SQSTM1/p62 and p-mTOR markers, and that microglia activation by clemastine might depend, at least in part, by autophagy.…”

Section: Discussionsupporting

confidence: 61%

Actions of the antihistaminergic clemastine on presymptomatic SOD1-G93A mice ameliorate ALS disease progression

Apolloni

Fabbrizio

Amadio

et al. 2016

J Neuroinflammation

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BackgroundAmyotrophic lateral sclerosis (ALS) is a disease with a strong neuroinflammatory component sustained by activated microglia contributing to motoneuron death. However, how to successfully balance neuroprotective versus neurotoxic actions by the use of antinflammatory agents is still under scrutiny. We have recently shown that the antihistamine clemastine, an FDA-approved drug, can influence the M1/M2 switch occurring in SOD1-G93A ALS microglia.MethodsHere, we have chronically treated female SOD1-G93A mice with clemastine, evaluated disease progression and performed mice lumbar spinal cord analysis at symptomatic and end stage of the disease. Moreover, we have studied the mechanism of action of clemastine in primary adult spinal SOD1-G93A microglia cultures and in NSC-G93A motor neuron-like cells.ResultsWe found that a short treatment with clemastine (50 mg/kg) from asymptomatic (postnatal day 40) to symptomatic phase (postnatal day 120) significantly delayed disease onset and extended the survival of SOD1-G93A mice by about 10 %. Under these conditions, clemastine induced protection of motor neurons, modulation of inflammatory parameters, reduction of SOD1 protein levels and SQSTM1/p62 autophagic marker, when analysed immediately at the end of the treatment (postnatal day 120). A long treatment with clemastine (from asymptomatic until the end stage) instead failed to ameliorate ALS disease progression. At the end stage of the disease, we found that clemastine short treatment decreased microgliosis and SOD1 protein and increased LC3-II autophagic marker, while the long treatment produced opposite effects. Finally, in spinal microglia cultures from symptomatic SOD1-G93A mice clemastine activated inflammatory parameters, stimulated autophagic flux via the mTOR signalling pathway and decreased SOD1 levels. Modulation of autophagy was also demonstrated in NSC34 SOD1-G93A motor neuron-like cells.ConclusionsBy gaining insights into the ameliorating actions of an antihistaminergic compound in ALS disease, our findings might represent an exploitable therapeutic approach for familial forms of ALS.

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Section: Discussionsupporting

confidence: 61%

Actions of the antihistaminergic clemastine on presymptomatic SOD1-G93A mice ameliorate ALS disease progression

Apolloni

Fabbrizio

Amadio

et al. 2016

J Neuroinflammation

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“…Neurobiological mechanisms of inflammation, protection, defence and repair comprise of networks of cells and molecular mediators that respond to alterations in homeostasis [25]. Neuroinflammation is inherent to an understanding of CNS responses after such alterations, for example exposure to ionising radiation.…”

Section: Microglial Responses To Stressors In the Cnsmentioning

confidence: 99%

“…The pro-inflammatory state of activated microglia, or the M1 type classical activation state, can be cytotoxic to surrounding cells, and when unregulated can propagate tissue damage and cause secondary injury [32], [33]. Correspondingly, neuroinflammation is thought to be implicated in multifarious functions and pathological states in the CNS, including the modulation of neurogenesis and neuronal development [25], [34], [35], synaptic stripping and neuronal dysfunction [36], [37], and is now widely implicated in the pathogenesis and progression of many neurodegenerative disorders [38], [39], [40], [41], [42], [43], [44], [45]. Alternatively, an M2 microglial activation state is not neurotoxic, transiently conferring neuroprotection and anti-inflammatory properties in response to injury [46].…”

Section: Microglial Responses To Stressors In the Cnsmentioning

confidence: 99%

The impact of high and low dose ionising radiation on the central nervous system

et al. 2016

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Responses of the central nervous system (CNS) to stressors and injuries, such as ionising radiation, are modulated by the concomitant responses of the brains innate immune effector cells, microglia. Exposure to high doses of ionising radiation in brain tissue leads to the expression and release of biochemical mediators of ‘neuroinflammation’, such as pro-inflammatory cytokines and reactive oxygen species (ROS), leading to tissue destruction. Contrastingly, low dose ionising radiation may reduce vulnerability to subsequent exposure of ionising radiation, largely through the stimulation of adaptive responses, such as antioxidant defences. These disparate responses may be reflective of non-linear differential microglial activation at low and high doses, manifesting as an anti-inflammatory or pro-inflammatory functional state. Biomarkers of pathology in the brain, such as the mitochondrial Translocator Protein 18 kDa (TSPO), have facilitated in vivo characterisation of microglial activation and ‘neuroinflammation’ in many pathological states of the CNS, though the exact function of TSPO in these responses remains elusive. Based on the known responsiveness of TSPO expression to a wide range of noxious stimuli, we discuss TSPO as a potential biomarker of radiation-induced effects.

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“…This is in clear contrast to the finding that autophagy is significantly reduced under both acute and chronic inflammatory conditions in microglia. For example, induction of autophagy activity by rapamycin has been shown to inhibit microglia over-activation, reduce the secretion of pro-inflammatory mediators, and provide protection against various insults in several animal models of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease [19] . It seems that autophagy plays different roles in macrophage and microglia in their inflammatory response.…”

Section: Regulation Of Inflammation Through the P38α Mapk-ulk1 Axismentioning

confidence: 99%

Autophagy in Inflammation: the p38α MAPK-ULK1 Axis

She

Zhao

et al. 2018

Macrophage

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The role of autophagy in modulation of neuroinflammation in microglia

Cited by 153 publications

References 114 publications

Actions of the antihistaminergic clemastine on presymptomatic SOD1-G93A mice ameliorate ALS disease progression

Actions of the antihistaminergic clemastine on presymptomatic SOD1-G93A mice ameliorate ALS disease progression

The impact of high and low dose ionising radiation on the central nervous system

Autophagy in Inflammation: the p38α MAPK-ULK1 Axis

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