Does Inflammation in an Autoimmune Disease Differ from Inflammation in Neurodegenerative Diseases? Possible Implications for Therapy

Schwartz, Michal; Butovsky, Oleg; Kipnis, Jonathan

doi:10.1007/s11481-005-9010-2

Cited by 15 publications

(11 citation statements)

References 79 publications

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“…A number of studies have provided evidence supporting the role of inflammation in the pathogenesis of neurodegenerative diseases (42,43). Specifically, known risk factors for PD, including aging (44), pesticide exposure (45), traumatic brain injury (46), the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (47), lysosomal storage diseases (48), and brain infection (49), can result in the activation of caspase-1.…”

Section: Discussionmentioning

confidence: 99%

Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein

Wang

Nguyen

Burlak

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

215

184

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The aggregation of α-synuclein (aSyn) leading to the formation of Lewy bodies is the defining pathological hallmark of Parkinson's disease (PD). Rare familial PD-associated mutations in aSyn render it aggregation-prone; however, PD patients carrying wild type (WT) aSyn also have aggregated aSyn in Lewy bodies. The mechanisms by which WT aSyn aggregates are unclear. Here, we report that inflammation can play a role in causing the aggregation of WT aSyn. We show that activation of the inflammasome with known stimuli results in the aggregation of aSyn in a neuronal cell model of PD. The insoluble aggregates are enriched with truncated aSyn as found in Lewy bodies of the PD brain. Inhibition of the inflammasome enzyme caspase-1 by chemical inhibition or genetic knockdown with shRNA abated aSyn truncation. In vitro characterization confirmed that caspase-1 directly cleaves aSyn, generating a highly aggregation-prone species. The truncation-induced aggregation of aSyn is toxic to neuronal culture, and inhibition of caspase-1 by shRNA or a specific chemical inhibitor improved the survival of a neuronal PD cell model. This study provides a molecular link for the role of inflammation in aSyn aggregation, and perhaps in the pathogenesis of sporadic PD as well.ver the past two decades, studies stimulated by the discovery of genetic mutations occurring in familial Parkinson's disease (PD) have generated a number of hypotheses concerning potential mechanisms of PD pathogenesis. Nonetheless, the causes and mechanism of sporadic PD, which constitutes the majority of cases, remain unknown.Before the genetic discoveries, epidemiologic evidence suggested environmental toxins, traumatic brain injury, and viral infection as potential causes of idiopathic PD (1-7). All of these insults could cause neural inflammation, a common feature of PD brains; however, whether neural inflammation contributes to the etiology of the disease or is part of its effect remained unclear. Suggestive evidence indicating the involvement of inflammation in the pathogenesis of PD emerged after an outbreak of encephalitis lethargica following the 1918 influenza pandemic, which killed approximately 1 million people and left many survivors with postencephalitic Parkinsonism (PEP). Affected persons presented with cardinal symptoms of typical Parkinson's disease, including stooped posture, masklike faces, muscular rigidity, and tremorous extremities. Contemporary cases of viral infection-associated Parkinsonism are rare, but both epidemiology and patient case studies indicate that infection-associated PD still occurs today (8-10).The role of viral infection in the pathogenesis of PD has been a controversial subject for more than 50 years. Proponents have pointed out the known close temporal association between infection and PEP, whereas opponents have cited studies that failed to find any viral remnants in the brains of affected patients. Moreover, there were no known routes for peripheral viral migration into the central nervous system (CNS). Recently, R. Smey...

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Section: Discussionmentioning

confidence: 99%

Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein

Wang

Nguyen

Burlak

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

215

184

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“…45,46,52,53 The dual role of glia cells during inflammation is unique but not necessarily perfectly balanced. The balance in the contrasting effects of glia cells (pro-vs. antiinflammatory) determines the nature of inflammation development.…”

Section: Introductionmentioning

confidence: 99%

Effects of olanzapine on LPS-induced inflammation in rat primary glia cells

Faour-Nmarne

Azab

2015

Innate Immun

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Olanzapine (OLZ) is an atypical antipsychotic drug that also has mood-stabilizing effects. The mechanism of action of OLZ is not fully understood. Accumulating data suggest that inflammation plays a role in the pathophysiology of mental disorders and that psychotropic drugs exhibit some anti-inflammatory properties. This study was undertaken to examine the effects of OLZ on LPS-induced inflammation in rat primary glia cells. Glia cells were extracted from newborn rat brains. OLZ (1 or 50 mM) was added to culture medium at 6 or 72 h before addition of LPS for another 18 h, and levels of IL-10, prostaglandin (PG) E 2 , NO and TNF-a, and expression of cyclo-oxygensase (COX)-2 and inducible NO synthase (iNOS) were determined. Treatment with 50 mM OLZ (but not 1 mM) significantly decreased LPS-induced secretion of IL-10, PGE 2 and TNF-a. In contrast, 50 mM OLZ significantly increased NO levels. OLZ did not alter the expression of COX-2 or iNOS in LPS-treated cells. These results suggest that OLZ differently affects the secretion of inflammatory mediators. Most of the significant effects of OLZ were obtained when 50 mM was used, which is a high and probably therapeutically irrelevant concentration. Therefore, under the conditions used in the present study OLZ seemed to lack a potent anti-inflammatory effect.

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“…Among glioma-infiltrating cells, microglia/macrophages represent the largest population, contributing to the total tumor mass by at least one third [16]. Under pathological conditions, these cells do not constitute a uniform cell population, but rather comprise a family of cells with diverse phenotypes and opposite biological activities: beneficial or, on the contrary, detrimental [17]. Macrophages and activated microglia, the latter defined as CNS macrophages, can be broadly divided into classically activated M1 cells, with cytotoxic properties, and alternatively activated M2 cells, with phagocytic activities.…”

Section: Introductionmentioning

confidence: 99%

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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Does Inflammation in an Autoimmune Disease Differ from Inflammation in Neurodegenerative Diseases? Possible Implications for Therapy

Cited by 15 publications

References 79 publications

Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein

Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein

Effects of olanzapine on LPS-induced inflammation in rat primary glia cells

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

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