Interferon-γ plays a role in paraquat-induced neurodegeneration involving oxidative and proinflammatory pathways

Mangano, Emily; Litteljohn, Darcy; So, Remmick; Nelson, Eric; Peters, Sarah; Bethune, Cheri; Bobyn, Jessica; Hayley, Shawn

doi:10.1016/j.neurobiolaging.2011.02.016

Cited by 77 publications

(81 citation statements)

References 95 publications

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“…Recent studies place IFN-g as a prime factor in inflammation-induced neurodegeneration (32)(33)(34). In correlation with this suggestion, we show that intraventricular injection with IFN-g results in upregulation of the expression of several chemokines and that pretreatment with the LXR agonist T1317 inhibits their induction.…”

Section: Discussionsupporting

confidence: 83%

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Reciprocal Negative Cross-Talk between Liver X Receptors (LXRs) and STAT1: Effects on IFN-γ–Induced Inflammatory Responses and LXR-Dependent Gene Expression

Pascual-García

Rué

León

et al. 2013

The Journal of Immunology

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Liver X receptors (LXRs) exert key functions in lipid homeostasis and in control of inflammation. In this study we have explored the impact of LXR activation on the macrophage response to the endogenous inflammatory cytokine IFN-γ. Transcriptional profiling studies demonstrate that ∼38% of the IFN-γ–induced transcriptional response is repressed by LXR activation in macrophages. LXRs also mediated inhibitory effects on selected IFN-γ–induced genes in primary microglia and in a model of IFN-γ–induced neuroinflammation in vivo. LXR activation resulted in reduced STAT1 recruitment to the promoters tested in this study without affecting STAT1 phosphorylation. A closer look into the mechanism revealed that SUMOylation of LXRs, but not the presence of nuclear receptor corepressor 1, was required for repression of the NO synthase 2 promoter. We have also analyzed whether IFN-γ signaling exerts reciprocal effects on LXR targets. Treatment with IFN-γ inhibited, in a STAT1-dependent manner, the LXR-dependent upregulation of selective targets, including ATP-binding cassette A1 (ABCA1) and sterol response element binding protein 1c. Downregulation of ABCA1 expression correlated with decreased cholesterol efflux to apolipoprotein A1 in macrophages stimulated with IFN-γ. The inhibitory effects of IFN-γ on LXR signaling did not involve reduced binding of LXR/retinoid X receptor heterodimers to target gene promoters. However, overexpression of the coactivator CREB-binding protein/p300 reduced the inhibitory actions of IFN-γ on the Abca1 promoter, suggesting that competition for CREB-binding protein may contribute to STAT1-dependent downregulation of LXR targets. The results from this study suggest an important level of bidirectional negative cross-talk between IFN-γ/STAT1 and LXRs with implications both in the control of IFN-γ–mediated immune responses and in the regulation of lipid metabolism.

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Section: Discussionsupporting

confidence: 83%

“…3A). Production of IFN-g contributes to the initiation and amplification of local immune responses, potentially leading to neurodegeneration in the CNS (32)(33)(34). We used a murine model of acute response to IFN-g based on injection of this cytokine in the ventricular region of the brain.…”

Section: Lxr Activation Transrepresses Selective Macrophage Transcripmentioning

confidence: 99%

Reciprocal Negative Cross-Talk between Liver X Receptors (LXRs) and STAT1: Effects on IFN-γ–Induced Inflammatory Responses and LXR-Dependent Gene Expression

Pascual-García

Rué

León

et al. 2013

The Journal of Immunology

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“…Moreover, mice deficient in dopamine (DA) receptor D3 (D3R), a receptor that favours IFN-γ production by CD4+ T-cells, are refractory to MPTP-induced neurodegeneration (Gonzalez et al 2013). Nevertheless, whilst IFN-γ-deficient mice display neuroprotection and attenuated microglial activation in MPTP and paraquat mouse models of PD (Mount et al 2007;Mangano et al 2012), the transference of spleen cells from IFN-γ-deficient mice into RAG1KO recipient mice did not protect against neuronal loss induced by MPTP (Brochard et al 2009). Interestingly, the same study proposed Fas-FasL interaction as a relevant mechanism favouring CD4+ T-cellmediated neurodegeneration, as transference of splenocytes from FasL-mutant mice into RAG1KO mice resulted in considerable protection against MPTP-induced neuronal loss (Brochard et al 2009).…”

Section: Role Of T-cells Infiltrating the Central Nervous System Parementioning

confidence: 99%

Regulation of the Neurodegenerative Process Associated to Parkinson’s Disease by CD4+ T-cells

González

Contreras

Pacheco

2015

J Neuroimmune Pharmacol

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Neuroinflammation constitutes a fundamental process involved in the physiopathology of Parkinson's disease (PD). Microglial cells play a central role in the outcome of neuroinflammation and consequent neurodegeneration of dopaminergic neurons in the substantia nigra. Current evidence indicates that CD4+ T-cells infiltrate the central nervous system (CNS) in PD, where they play a critical role determining the functional phenotype of microglia, thus regulating the progression of the neurodegenerative process. Here, we first analysed the pathogenic role of inflammatory phenotypes and the beneficial role of anti-inflammatory phenotypes of encephalitogenic CD4+ T-cells involved in the physiopathology of PD. Next, we discussed how alterations of neurotransmitter levels observed in the basal ganglia throughout the time course of PD progression could be strongly affecting the behaviour of encephalitogenic CD4+ T-cells and thereby the outcome of the neuroinflammatory process and the consequent neurodegeneration of dopaminergic neurons. Afterward, we integrated the evidence indicating the involvement of an antigen-specific immune response mediated by T-cells and B-cells against CNS-derived self-constituents in PD. Consistent with the involvement of a relevant autoimmune component in PD, we also reviewed the polymorphisms of both, class I and class II major histocompatibility complexes, associated to the risk of PD. Overall, this study gives an overview of how an autoimmune component involved in PD plays a fundamental role in the progression of the neurodegenerative process.

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“…Paraquat toxicity also is known to involve mitochondrial dysfunction, excessive NMDA activity, oxidative stress, elevated in�ammatory cytokines and elevated NF-B activity [142][143][144][145][146][147], raising a possible role for all of these NO/ONOO − cycle elements in the generation of paraquatdependent PAH.…”

Section: Principlementioning

confidence: 99%

Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review

Pall

2013

ISRN Hypertension

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e NO/ONOO − cycle is a primarily local biochemical/physiological vicious cycle that appears to cause a series of chronic in�ammatory diseases. is paper focuses on whether the cycle causes pulmonary arterial hypertension (PAH) when located in the pulmonary arteries. e cycle involves 12 elements, including superoxide, peroxynitrite (ONOO − ), nitric oxide (NO), oxidative stress, NF-B, in�ammatory cytokines, iNOS, mitochondrial dysfunction, intracellular calcium, tetrahydrobiopterin depletion, NMDA activity, and TRP receptor activity. 10 of the 12 are elevated in PAH (NMDA?, NO?) and 11 have documented causal roles in PAH. Each stressor that initiates cases of PAH acts to raise cycle elements, and may, therefore, initiate the cycle in this way. PAH involves a primarily local mechanism as required by the cycle and the symptoms and signs of PAH are generated by elements of the cycle. Endothelin-1, which acts as a causal factor in PAH, acts as part of the cycle; its synthesis is stimulated by cycle elements, and it, in turn, increases each element of the cycle. is extraordinary �t to the principles of the NO/ONOO − cycle allows one to conclude that PAH is a NO/ONOO − cycle disease, and this �t supports the cycle as a ma�or paradigm of chronic in�ammatory disease.

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Interferon-γ plays a role in paraquat-induced neurodegeneration involving oxidative and proinflammatory pathways

Cited by 77 publications

References 95 publications

Reciprocal Negative Cross-Talk between Liver X Receptors (LXRs) and STAT1: Effects on IFN-γ–Induced Inflammatory Responses and LXR-Dependent Gene Expression

Reciprocal Negative Cross-Talk between Liver X Receptors (LXRs) and STAT1: Effects on IFN-γ–Induced Inflammatory Responses and LXR-Dependent Gene Expression

Regulation of the Neurodegenerative Process Associated to Parkinson’s Disease by CD4+ T-cells

Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review

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Interferon-γ plays a role in paraquat-induced neurodegeneration involving oxidative and proinflammatory pathways

Cited by 77 publications

References 95 publications

Reciprocal Negative Cross-Talk between Liver X Receptors (LXRs) and STAT1: Effects on IFN-γ–Induced Inflammatory Responses and LXR-Dependent Gene Expression

Reciprocal Negative Cross-Talk between Liver X Receptors (LXRs) and STAT1: Effects on IFN-γ–Induced Inflammatory Responses and LXR-Dependent Gene Expression

Regulation of the Neurodegenerative Process Associated to Parkinson’s Disease by CD4+ T-cells

Pulmonary Hypertension Is a Probable NO/ONOO−Cycle Disease: A Review

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Product

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Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review