CNS-Targeted Production of IL-17A Induces Glial Activation, Microvascular Pathology and Enhances the Neuroinflammatory Response to Systemic Endotoxemia

Zimmermann, Julian; Krauthausen, Marius; Höfer, Markus; Heneka, Michael T.; Campbell, Iain L.; Müller, Marcus

doi:10.1371/journal.pone.0057307

Cited by 66 publications

(46 citation statements)

References 90 publications

(100 reference statements)

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“…We found that IL-17A alone was able to drive a psoriatic response in the skin [12] that led to an associated cardiovascular disease [37]. Similarly, Müller et al [101] overexpressed IL-17A as a transgene driven by the GFAP promoter specific for astrocytes in the CNS. Placing IL-17A in high levels in the CNS proved informative: the authors found that IL-17A expression alone was able to activate glial cells and enhance neuroinflammatory responses, thus showing that CNS cells express a functional IL-17RA/C receptor complex.…”

Section: Il-17 Function In the Cnsmentioning

confidence: 56%

The role of IL-17 in CNS diseases

2015

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Cytokines of the IL-17 family are uniquely placed on the border between immune cells and tissue. Although IL-17 was originally found to induce the activation and mobilization of neutrophils to sites of inflammation, its tissue-specific function is not yet fully understood. The best-studied IL-17 family members, IL-17A and IL-17F, are both typically produced by immune cells such as Th17, γδ T cells and innate lymphoid cells group 3. However, the cells that respond to these cytokines are mostly found in inflamed tissue. As seen in psoriatic skin lesions or in joints of rheumatoid arthritis patients, high levels of IL-17 have been detected in the central nervous system (CNS) during inflammatory responses. Here, we provide a general review of the molecular function of IL-17 and its role in the CNS in particular. Of the different inflammatory conditions of the CNS, we found multiple sclerosis (MS) to be the one most associated with the presence of Th17 cells and IL-17. In particular, many studies using the murine model for MS, experimental autoimmune encephalomyelitis, found a clear association of Th17 and IL-17 with disease severity and progression. We summarize the recent advances made in correlating the presence of IL-17 with impaired blood-brain barrier integrity as well as the activation of astrocytes and microglia and the consequences for disease progression. There is also evidence that IL-17 plays a pathogenic role in the post-ischemic phase of stroke as well as its experimental model. We review the limited but promising data on the sources of post-stroke IL-17 production and its effects on CNS-resident target cells. In addition to MS and stroke, there is also evidence linking high levels of IL-17 to depression, as a frequent comorbidity of several inflammatory diseases, as well as to different types of infections of the CNS. The evidence we supply here suggests that inhibiting the function of the IL-17 cytokine family could have a beneficial effect on pathogenic conditions in the CNS.

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Section: Il-17 Function In the Cnsmentioning

confidence: 56%

The role of IL-17 in CNS diseases

2015

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“…As well, using linear regression, IL-17 is a significant predictor for unchanged cases. Chronic IL-17 exposure can induce chronic vascular changes such as basement membrane thickening without a loss of integrity of the blood-retinal barrier [16]. These changes may impede the effect of VEGF inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Serum cytokines as biomarkers for age-related macular degeneration

Nassar

Grisanti

Elfar

et al. 2014

Graefes Arch Clin Exp Ophthalmol

100

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“…Identification of AEG-1 as a downstream target of IL-1β and TNF-α, along with its regulation of NF-κB signaling, implies that AEG-1 is a key component of autocrine inflammatory signaling in astrocytes. Astrocyte production of IL-17A, IL-6, IL-12 and CXCL10 induce significant neuroglial activation (Pagenstecher et al , 2000; Zimmermann et al , 2013). Disrupting astrocyte-derived inflammatory signaling and cytokine production in a rat model of neuroinflammation, resulted in attenuated neuro/glial activation (Soliman et al , 2013).…”

Section: Aeg-1 In Handmentioning

confidence: 99%

Astrocyte elevated gene-1 (AEG-1) and the A(E)Ging HIV/AIDS-HAND

Vartak-Sharma

Nooka

Ghorpade

2017

Progress in Neurobiology

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Recent attempts to analyze human immunodeficiency virus (HIV)-1-induced gene expression changes in astrocytes uncovered a multifunctional oncogene, astrocyte elevated gene-1 (AEG-1). Our previous studies revealed that AEG-1 regulates reactive astrocytes proliferation, migration and inflammation, all hallmarks of aging and CNS injury. Moreover, the involvement of AEG-1 in neurodegenerative disorders, such as Huntington’s disease and migraine, and its induction in the aged brain suggest a plausible role in regulating overall CNS homeostasis and aging. Therefore, it is important to investigate AEG-1 specifically in aging-associated cognitive decline. In this study, we decipher the common mechanistic links in cancer, aging and HIV-1-associated neurocognitive disorders that likely contribute to AEG-1-based regulation of astrocyte responses and function. Despite AEG-1 incorporation into HIV-1 virions and its induction by HIV-1, tumor necrosis factor-α and interleukin-1β, the specific role(s) of AEG-1 in astrocyte-driven HIV-1 neuropathogenesis are incompletely defined. We propose that AEG-1 plays a central role in a multitude of cellular stress responses involving mitochondria, endoplasmic reticulum and the nucleolus. It is thus important to further investigate AEG-1-based cellular and molecular regulation in order to successfully develop better therapeutic approaches that target AEG-1 to combat cancer, HIV-1 and aging.

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CNS-Targeted Production of IL-17A Induces Glial Activation, Microvascular Pathology and Enhances the Neuroinflammatory Response to Systemic Endotoxemia

Cited by 66 publications

References 90 publications

The role of IL-17 in CNS diseases

The role of IL-17 in CNS diseases

Serum cytokines as biomarkers for age-related macular degeneration

Astrocyte elevated gene-1 (AEG-1) and the A(E)Ging HIV/AIDS-HAND

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