The influence of AAV2-mediated gene transfer of human IL-10 on neurodegeneration and immune response in a murine model of Parkinson's disease

Joniec-Maciejak, Ilona; Ciesielska, Agnieszka; Wawer, Adriana; Sznejder-Pachołek, Anna; Schwenkgrub, Joanna; Cudna, Agnieszka; Hadaczek, Piotr; Bankiewicz, K.S.; Członkowska, Anna; Członkowski, Andrzej

doi:10.1016/j.pharep.2014.03.008

Cited by 39 publications

(28 citation statements)

References 37 publications

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“…Such a scenario confers the assurance of neuroinflammation and also depicts the involvement of these cell types in brain inflammation. Earlier reports have documented that, in the PD brain, the quantity of inflammatory markers, such as IL-6, transforming growth factor beta (TGF-β), and IL-1, increases significantly [33,34]. Moreover, MDSCs are reported to induce the CD4+ T cells to transform into Th17 cell types under certain condition [18, 35].…”

Section: Discussionmentioning

confidence: 99%

Increased Levels of Pro-Inflammatory and Anti-Inflammatory Cellular Responses in Parkinson’s Disease Patients: Search for a Disease Indicator

Yang¹,

Guo

Zhu³

et al. 2017

Med Sci Monit

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BackgroundParkinson’s disease (PD) is the second most prevalent neurodegenerative disorder and it arises when most of the dopaminergic neurons of substantia nigra region die. Several mechanisms have been postulated as the causative event in PD pathology, and neuroinflammation is most crucial among them.Material/MethodsWe analyzed T-helper 17 (Th17) cells and myeloid-derived suppressor cells (MDSCs) from 80 PD patients to assess inflammatory processes and to find a cost-effective means to evaluate PD prognosis.ResultsWe found significantly increased numbers of Th17 cells and MDSCs count in peripheral circulation in PD patients compared with controls (p<0.001). A positive correlation was found between Th17 cells and MDSCs in PD patients (r=0.421, p<0.05).ConclusionsOur results show the effector role of Th17 cells and MDSCs in PD pathology and shows their utility as effective biomarkers for PD diagnosis.

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Section: Discussionmentioning

confidence: 99%

Increased Levels of Pro-Inflammatory and Anti-Inflammatory Cellular Responses in Parkinson’s Disease Patients: Search for a Disease Indicator

Yang¹,

Guo

Zhu³

et al. 2017

Med Sci Monit

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“…Cerebral infusion of AAV-expressing human IL-10 in a MPTP mouse model of PD decreases the expression of pro-inflammatory iNOS and importantly enhances the levels of anti-inflammatory mediators including IFN-γ and transforming growth factor-β (TGF-β). Infusion of AAV-expressing human IL-10 prevents the loss of striatal DA and reduces TH transcriptome levels suggesting neuroprotection in MPTP intoxicated mice (Schwenkgrub et al, 2013; Joniec-Maciejak et al, 2014). …”

Section: Regulators Of Microglial Activation Statesmentioning

confidence: 99%

Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson’s Disease

Subramaniam

Federoff

2017

Front. Aging Neurosci.

277

240

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Parkinson’s disease (PD) is a chronic and progressive disorder characterized neuropathologically by loss of dopamine neurons in the substantia nigra, intracellular proteinaceous inclusions, reduction of dopaminergic terminals in the striatum, and increased neuroinflammatory cells. The consequent reduction of dopamine in the basal ganglia results in the classical parkinsonian motor phenotype. A growing body of evidence suggest that neuroinflammation mediated by microglia, the resident macrophage-like immune cells in the brain, play a contributory role in PD pathogenesis. Microglia participate in both physiological and pathological conditions. In the former, microglia restore the integrity of the central nervous system and, in the latter, they promote disease progression. Microglia acquire different activation states to modulate these cellular functions. Upon activation to the M1 phenotype, microglia elaborate pro-inflammatory cytokines and neurotoxic molecules promoting inflammation and cytotoxic responses. In contrast, when adopting the M2 phenotype microglia secrete anti-inflammatory gene products and trophic factors that promote repair, regeneration, and restore homeostasis. Relatively little is known about the different microglial activation states in PD and a better understanding is essential for developing putative neuroprotective agents. Targeting microglial activation states by suppressing their deleterious pro-inflammatory neurotoxicity and/or simultaneously enhancing their beneficial anti-inflammatory protective functions appear as a valid therapeutic approach for PD treatment. In this review, we summarize microglial functions and, their dual neurotoxic and neuroprotective role in PD. We also review molecules that modulate microglial activation states as a therapeutic option for PD treatment.

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“…To mention a few examples, a role for IL-10 in attenuating local inflammatory reactions during permanent ischemia has been described [70]. Also, adenoviral-mediated expression of human IL-10 in the striatum of mice subjected to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicant model of Parkinson’s disease decreased the neurodegenerative effect of MPTP administration [71]. Importantly, the benefits of dampening neuroinflammation are highly dependent on the disease type.…”

Section: Neuroprotection Vs Neurodegeneration: a Role For Il-10 In Timentioning

confidence: 99%

Balancing the immune response in the brain: IL-10 and its regulation

Lobo-Silva

Carriche

Castro

et al. 2016

J Neuroinflammation

328

199

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BackgroundThe inflammatory response is critical to fight insults, such as pathogen invasion or tissue damage, but if not resolved often becomes detrimental to the host. A growing body of evidence places non-resolved inflammation at the core of various pathologies, from cancer to neurodegenerative diseases. It is therefore not surprising that the immune system has evolved several regulatory mechanisms to achieve maximum protection in the absence of pathology.Main bodyThe production of the anti-inflammatory cytokine interleukin (IL)-10 is one of the most important mechanisms evolved by many immune cells to counteract damage driven by excessive inflammation. Innate immune cells of the central nervous system, notably microglia, are no exception and produce IL-10 downstream of pattern recognition receptors activation. However, whereas the molecular mechanisms regulating IL-10 expression by innate and acquired immune cells of the periphery have been extensively addressed, our knowledge on the modulation of IL-10 expression by central nervous cells is much scattered. This review addresses the current understanding on the molecular mechanisms regulating IL-10 expression by innate immune cells of the brain and the implications of IL-10 modulation in neurodegenerative disorders.ConclusionThe regulation of IL-10 production by central nervous cells remains a challenging field. Answering the many remaining outstanding questions will contribute to the design of targeted approaches aiming at controlling deleterious inflammation in the brain.

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The influence of AAV2-mediated gene transfer of human IL-10 on neurodegeneration and immune response in a murine model of Parkinson's disease

Abstract: Our data suggest that the transfer of AAV2-hIL-10 into the striatum may play a neuroprotective role in the mouse MPTP model of PD and these effects are mediated by the anti-inflammatory action of IL-10.

Cited by 39 publications

References 37 publications

Increased Levels of Pro-Inflammatory and Anti-Inflammatory Cellular Responses in Parkinson’s Disease Patients: Search for a Disease Indicator

Increased Levels of Pro-Inflammatory and Anti-Inflammatory Cellular Responses in Parkinson’s Disease Patients: Search for a Disease Indicator

Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson’s Disease

Balancing the immune response in the brain: IL-10 and its regulation

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