mTOR kinase, a key player in the regulation of glial functions: Relevance for the therapy of multiple sclerosis

Russo, Cinzia Dello; Lisi, Lucia; Feinstein, Douglas L.; Navarra, Pierluigi

doi:10.1002/glia.22433

Cited by 82 publications

(57 citation statements)

References 111 publications

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“…Data from our group and others support the notion that mTOR is involved in glial proinflammatory activation [13-15]. In particular, we have demonstrated that mTOR inhibitors reduce iNOS expression and activity induced by cytokines, but not those induced by lipopolysaccharide (LPS), in primary rat microglia [13].…”

Section: Introductionsupporting

confidence: 61%

The mTOR kinase inhibitors polarize glioma-activated microglia to express a M1 phenotype

Lisi¹,

Laudati²,

Navarra³

et al. 2014

J Neuroinflammation

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BackgroundIncreased activation of mammalian target of rapamycin (mTOR) is observed in numerous human cancers. Recent studies on the glioma kinome have identified several deregulated pathways that converge and activate mTOR. The available evidence on the role of microglia in CNS cancers would suggest a dual role, a tumoricidal role and -on the contrary- a role favoring tumor growth.MethodsIn the present paper, we have compared the effects of μM concentrations of rapamycin (RAPA) and its analog, RAD001 (RAD), on activated microglia; the latter was obtained by exposing cells to conditioned medium harvested either from inflammatory activated glioma cells (LI-CM) or from glioma cells kept under basal conditions (C-CM).ResultsHere we show that the inhibition of mTOR polarizes glioma-activated microglial cells towards the M1 phenotype, with cytotoxic activities, preventing the induction of the M2 status that promotes tumor growth. In fact RAPA and RAD significantly increased iNOS expression and activity, while on the same time significantly reducing IL-10 gene expression induced by C-CM, thus suggesting that the drugs prevent the acquisition of a M2 phenotype in response to glioma factors promoting a classic M1 activation. Similar results were obtained using the conditioned media obtained after glioma stimulation with LPS-IFNγ (LI-CM), which was found to induce a mixture of M1 and M2a/b polarization phenotypes. In these conditions, the inhibition of mTOR led to a significant up-regulation of iNOS, and in parallel to the down-regulation of both ARG and IL-10 gene expression.ConclusionsThese data suggest that mTOR inhibition may prevent glioma induced M2 polarization of microglial cells and increase their cytotoxic potential, possibly resulting in antitumor actions.

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Section: Introductionsupporting

confidence: 61%

The mTOR kinase inhibitors polarize glioma-activated microglia to express a M1 phenotype

Lisi¹,

Laudati²,

Navarra³

et al. 2014

J Neuroinflammation

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“…Although most studies assessing the role of autophagy in neurodegeneration and aging have focused on neurons, emerging work suggests that autophagy may also contribute to glial cell function [85,86]. Here we will focus on microglia, the major player of the innate immune system in the brain.…”

Section: Autophagy In Microgliamentioning

confidence: 99%

Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging

Plaza-Zabala

Sierra-Torre

Sierra

2017

IJMS

265

210

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Abstract:Autophagy is emerging as a core regulator of Central Nervous System (CNS) aging and neurodegeneration. In the brain, it has mostly been studied in neurons, where the delivery of toxic molecules and organelles to the lysosome by autophagy is crucial for neuronal health and survival. However, we propose that the (dys)regulation of autophagy in microglia also affects innate immune functions such as phagocytosis and inflammation, which in turn contribute to the pathophysiology of aging and neurodegenerative diseases. Herein, we first describe the basic concepts of autophagy and its regulation, discuss key aspects for its accurate monitoring at the experimental level, and summarize the evidence linking autophagy impairment to CNS senescence and disease. We focus on acute, chronic, and autoimmunity-mediated neurodegeneration, including ischemia/stroke, Alzheimer's, Parkinson's, and Huntington's diseases, and multiple sclerosis. Next, we describe the actual and potential impact of autophagy on microglial phagocytic and inflammatory function. Thus, we provide evidence of how autophagy may affect microglial phagocytosis of apoptotic cells, amyloid-β, synaptic material, and myelin debris, and regulate the progression of age-associated neurodegenerative diseases. We also discuss data linking autophagy to the regulation of the microglial inflammatory phenotype, which is known to contribute to age-related brain dysfunction. Overall, we update the current knowledge of autophagy and microglia, and highlight as yet unexplored mechanisms whereby autophagy in microglia may contribute to CNS disease and senescence.

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“…Genetic evidence also indicates the important role of mTOR in Th17 cell differentiation [20,21]. In agreement with these observations, rapamycin treatment ameliorates the clinical course of EAE [22-24]. Given the similar effects of blocking mTOR, HIF1α and glycolysis on Th17 cell differentiation and the relationship between these pathways, these studies highlight the important roles of the mTOR-HIF1α-glycolysis axis in Th17 cell differentiation.…”

Section: Introductionmentioning

confidence: 54%

Metabolic Control of Th17 Cell Generation and CNS Inflammation

Yang

Chi

2013

J Neurol Neurophysiol

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Multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), results from uncontrolled auto reactive T cells that infiltrate the CNS and attack the myelin sheath. Th17 cells play a prominent role in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Extensive studies have focused on understanding the roles of cytokine signaling and transcriptional network in the differentiation of Th17 cells and their pathogenicity in CNS inflammation. Aside from these events, activated T cells dynamically reprogram their metabolic pathways to fulfill the bioenergic and biosynthetic requirements for proper T cell functions. Emerging evidence indicates that modulation of these metabolic pathways impinges upon the differentiation of Th17 cells and the pathogenesis of EAE. Thus, a better understanding of the functions and mechanisms of T cell metabolism in Th17 cell biology may provide new avenues for therapeutic targeting of MS. In this review, we discuss the recent advances in our understanding of T cell metabolic pathways involved in Th17 cell differentiation and CNS inflammation.

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mTOR kinase, a key player in the regulation of glial functions: Relevance for the therapy of multiple sclerosis

Cited by 82 publications

References 111 publications

The mTOR kinase inhibitors polarize glioma-activated microglia to express a M1 phenotype

The mTOR kinase inhibitors polarize glioma-activated microglia to express a M1 phenotype

Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging

Metabolic Control of Th17 Cell Generation and CNS Inflammation

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