Inhibitory effect of IL-17 on neural stem cell proliferation and neural cell differentiation

Abstract

BackgroundIL-17, a Th17 cell-derived proinflammatory molecule, has been found to play an important role in the pathogenesis of autoimmune diseases, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). While IL-17 receptor (IL-17R) is expressed in many immune-related cells, microglia, and astrocytes, it is not known whether IL-17 exerts a direct effect on neural stem cells (NSCs) and oligodendrocytes, thus inducing inflammatory demyelination in the central nervous system.MethodsWe first detected IL-17 receptor expression in NSCs with immunostaining and real time PCR. We then cultured NSCs with IL-17 and determined NSC proliferation by neurosphere formation capability and cell number count, differentiation by immunostaining neural specific markers, and apoptosis of NSCs by flow cytometry.ResultsNSCs constitutively express IL-17R, and when the IL-17R signal pathway was activated by adding IL-17 to NSC culture medium, the number of NSCs was significantly reduced and their ability to form neurospheres was greatly diminished. IL-17 inhibited NSC proliferation, but did not induce cytotoxicity or apoptosis. IL-17 hampered the differentiation of NSCs into astrocytes and oligodendrocyte precursor cells (OPCs). The effects of IL-17 on NSCs can be partially blocked by p38 MAPK inhibitor.ConclusionsIL-17 blocks proliferation of NSCs, resulting in significantly reduced numbers of astrocytes and OPCs. Thus, in addition to its proinflammatory role in the immune system, IL-17 may also play a direct role in blocking remyelination and neural repair in the CNS.

Effect of Fingolimod on Neural Stem Cells: A Novel Mechanism and Broadened Application for Neural Repair

“…Pro-inflammatory cytokines (e.g., interleukin-17 and interferon g [IFN-g]) released by splenocytes of EAE mice ( Figure S3A) are reported to have an inhibitory effect on NSC proliferation and neural cell differentiation. 34 Our results here showed that NSC differentiation to OLGs was significantly suppressed in the presence of culture supernatants from PLP-specific splenocytes, as shown by decreased cell survival ( Figure S3B), reduced OLG number (CNPase + cells) (Figure S3C), and less OLG arborization (Figures S3D and S3E) compared with PBS-treated controls. However, this impairment of NSC differentiation was overcome by FTY720 (1 nM) ( Figure S3), demonstrating the protective effect of FTY720 during NSC differentiation into OLGs under pathological conditions and possibly during remyelination of already-damaged CNS tissues in MS.…”

The role of IL-17 in CNS diseases

“…Previous observations are mechanistically supported by in vitro findings, which demonstrate Th17-induced neuronal injury mediated by deleterious elevations of intracellular Ca 2+ levels in neurons. Indeed, basal expression of the IL-17RA has been shown for various neuronal populations [10,54], and it can be potently up-regulated in pathological conditions such as, for example, focal cortical dysplasia [29]. One particularly sensitive target for IL-17A-mediated neuronal damage is the neural stem cells (NSCs) of the subventricular and subgranular zone of the hippocampus.…”

“…The addition of IL-17 to NSC cultures does not induce apoptosis in these cells but markedly suppresses neurosphere growth in vitro. Moreover, IL-17A inhibits NSC proliferation in a p38 MAPK-dependent manner and constrains NSC differentiation, especially into astrocytic and NG2 lineages [54]. However, IL-17A can also have neurotrophic properties.…”

Control of autoimmune CNS inflammation by astrocytes

“…Taken together, astrocyte-intrinsic IL-17A mediated signaling seems to promote CNS inflammation. However, recent conflicting data concerning the effects of IL-17A on neuronal stem cells and oligodendrocyte precursor cells(25) highlight the need for further investigations before targeting this immune axis in cell-type specific therapies for Multiple Sclerosis.…”