IL‐17A activates ERK1/2 and enhances differentiation of oligodendrocyte progenitor cells

Abstract

Inflammatory signals present in demyelinated multiple sclerosis lesions affect the reparative remyelination process conducted by oligodendrocyte progenitor cells (OPCs). Interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin (IL)–6 have differing effects on the viability and growth of OPCs, however the effects of IL-17A are largely unknown. Primary murine OPCs were stimulated with IL-17A and their viability, proliferation, and maturation were assessed in culture. IL-17A-stimulated OPCs exited the cell cycle and differentiated with no loss in viability. Expression of the myelin-specific protein, proteolipid protein, increased in a cerebellar slice culture assay in the presence of IL-17A. Downstream, IL-17A activated ERK1/2 within 15 min and induced chemokine expression in 2 days. These results demonstrate that IL-17A exposure stimulates OPCs to mature and participate in the inflammatory response.

Intracranial IL-17A overexpression decreases cerebral amyloid angiopathy by upregulation of ABCA1 in an animal model of Alzheimer’s disease

“…Given that soluble Aβ levels in the hippocampus and CSF were similarly decreased in the IL-17A-overexpressing mice and neurons in the hippocampus highly expressed IL-17A by the rAAV5 gene delivery, we infer that IL-17A secreted from neurons induced ABCA1 expression in brain endothelial. Because IL-17A can induce activation of ERK1/2 signal (Guo et al , 2014; Rodgers et al , 2015; Song et al , 2015) and because ERK1/2 signaling regulates ABCA1 expression in different types of cells (Chang et al , 2013; Mulay et al , 2013), we determined if IL-17A would increase ABCA1 expression via ERK1/2 activation in endothelial bEnd.3 cells. As expected, IL-17A increased phospho-ERK1/2 but not total ERK1/2.…”

Intracellular signaling pathway regulation of myelination and remyelination in the CNS

“…Phosphorylation of AKT and IkB was unchanged after stimulation with IL-17A, suggesting that this cytokine specifically activates the ERK/MAPK pathway. Although the results did not reach significance, there was a clear trend toward a reversal of the enhanced OPC differentiation phenotype after treatment with an ERK inhibitor, supporting that IL-17A is promoting OPC differentiation through the ERK pathway (Rodgers et al, 2015). In another study, TAPP1, a PH domain-containing adapter protein, was knocked down in primary OPC cultures resulting in increased levels of both total and activated ERK1/2 protein along with enhanced OPC differentiation (Chen et al, 2015).…”

“…Additionally, several recent studies have demonstrated a strong correlation between increased ERK activity and OPC differentiation. IL-17A, a cytokine found in active MS lesions was shown to increase both ERK1/2 activity and OPC differentiation when applied to cerebellar slice cultures (Rodgers et al, 2015). Phosphorylation of AKT and IkB was unchanged after stimulation with IL-17A, suggesting that this cytokine specifically activates the ERK/MAPK pathway.…”

Demyelination as a rational therapeutic target for ischemic or traumatic brain injury

“…Furthermore, IL-6 enhances OPC differentiation and survival even in the presence of glutamate excitotoxicity (Pizzi et al, 2004; Valerio et al, 2002). Recent studies demonstrate that IL-17A exposure stimulates OPCs to differentiate and mature and participate in the inflammatory response (Rodgers et al, 2014). An improved understanding of inflammatory mechanisms underlying oligodendrocyte death and demyelination might lead to novel neuroprotective therapeutic approaches for stroke or TBI patients.…”