NSCs are a unique population of cells that exhibit stem cell properties, including self-renewal (production of a large number of progeny) and multipotency (differentiation of the progeny into the three primary CNS phenotypes: neurons, astrocytes and oligodendrocytes) . NSCs that have been isolated from adult brain can be maintained in vitro for extended periods of time without losing their proliferation or differentiation potential [22, 23]. Because NSCs have the ability to support neurogenesis within restricted areas throughout adulthood and can undergo extensive in vitro expansion, they have been proposed as a renewable source of neural precursors for regenerative transplantation in various CNS diseases, including degenerative disorders, injury and cancer [24, 25] and EAE [21, 26, 27]. These cells reached multiple demyelinating areas of the CNS and ameliorated EAE clinically and pathologically to a similar extent when injected either intravenously or intraventricularly . However, in inflamed foci, such as occur in MS and EAE, which are a hostile microenvironment for NSCs, the migration and proliferation of NSCs are inhibited, resulting in a failure of spontaneous remyelination and neural repair . It is thus important to identify immune cells and/or proinflammatory mediators that are responsible for this pathogenic outcome.
IL-17A, which has been called IL-17, is the prototypical cytokine of the IL-17 family, which comprises IL-17A-F . IL-17A and IL-17F trigger signaling via their receptor, a heterodimeric molecule composed of IL-17RA and IL-17RC . IL-17 activates NFκB signaling and induces several proinflammatory cytokines and chemokines, in particular, CCL20, which can attract CCR6-expressing Th17 cells . In the CNS, IL-17 activates microglial cells  and induces oligodendrocyte cell death ; it is thus pathogenic in CNS inflammatory demyelination. However, the role of IL-17 signaling in NSCs is not yet known. This question is important given the critical role of these cells in remyelination and neural repair following brain damage. The capacity of NSCs for self-renewal and for generating functional differentiated cells makes them an attractive potential therapeutic tool for the treatment of neurological disorders. Indeed, NSCs have recently emerged as a potential therapeutic approach in the treatment of MS . In the present study, we demonstrate that IL-17 significantly reduces NSC number by inhibiting the proliferation of these cells, and is thus a novel mechanism underlying the pathogenesis of Th17 cells in the development of CNS inflammatory demyelinating diseases such as MS.
Previous studies have shown that IL-17/IL-17R interactions use TRAF6 to transduce its signal in immune cells , and is a well-studied multi-pathway process of cell death in neural cells . At the same time, IL-17 mediated activation of JNK1/2 is reported to be involved in cell death [34, 35]. Moreover, IL-17R has been found to express in oligodendrocytes, the myelinating cells, and adding IL-17 to culture induces significant oligodendrocyte apoptosis . We hypothesized that NSC apoptosis would be increased after treatment with IL-17. To this end, we tested whether IL-17 had induced NSC apoptosis. Surprisingly, our findings showed that, compared with control, apoptosis in treated NSCs had decreased. Further, we also investigated whether this proinflammatory mediator induced cytotoxicity of these cells, which is an important pathway involved in cell death [36, 37]. Similarly, IL-17 did not induce lactate dehydrogenase (LDH) release, which is a reliable and simple approach for defining cell death . Together, these results indicate that the decrease in cell number in treated NSCs resulted from cell proliferation inhibition, not cell death.
The mitogen activated protein kinase (MAPK) family is composed of three main members, including JNK, ERK and p38 MAPK, which can translocate from cytoplasm to nucleus, and induce a series of inflammatory actions in cells . Among them, the interaction between p38 MAPK and IL-17 is well known for its important role in immunity. For example, IL-17 stimulation induced a high level of proinflammatory cytokine production via the Erk1/2, p38 MAPK, PI3K/Akt, and NF-κB pathways . On the other hand, activation of p38 MAPK signaling pathway is essential for in vitro and in vivo IL-17 production, and is required for the development and progression of CNS proinflammatory demyelination . p38 MAPK signaling has also been found to be involved in insufficient NSC proliferation; targeting p38 restored these cells and corrected neuromotor deficits in an ataxia-telangiectasia mouse model . The importance of p38 MAPK activation in the inhibition of NSC proliferation has also been observed by culturing NSCs with IL-1β, another proinflammatory cytokine that is involved in CNS proinflammatory demyelination . We demonstrated that the p38 MAPK level in NSCs increased after IL-17 stimulation and that p38 MAPK inhibitor can release the anti-proliferation effect of IL-17. We also showed that the inhibition of NSC proliferation by IL-17 can be partially reversed by p38 MAPK inhibitor. Thus, in addition to its proinflammatory role in the immune system, IL-17 also play a direct role in blocking myelination and neural repair in EAE/MS though the MAPK pathway.
The capacity of NSCs for neural cell differentiation makes these cells a promising potential therapeutic tool for the treatment of nervous system disorders [1, 2]. Increasing evidence suggests that NSCs go through a process of self-renewal, proliferating and differentiating into the appropriate lineage when inflammatory damage or injury occurs in the nervous system . To determine the functions of IL-17 on NSC differentiation, we investigated whether IL-17 might hamper the capacity of NSCs to differentiate into neurons, astrocytes and OPCs. While IL-17 stimulation drove NSCs to differentiate into a smaller number of neurons, astrocytes, it resulted in significantly lower numbers of NSCs differentiating into astrocytes and OPCs, cells crucial for remyelination , as well as undifferentiated NSCs. Given that OPCs are the precursor cells of oligodendrocytes, the only myelinating cells in the CNS, reduced OPC differentiation from NSCs could be a potential mechanism of IL-17 pathogenesis in the failure of remyelination in MS/EAE . Further, given that astrocytes play an important role in the production of neurotrophic factors and support neural repair , reduction of these cells by IL-17 would result in incomplete neural repair after CNS damage. These results, combined with the proinflammatory effect of IL-17 in the peripheral immune system and in the CNS, represent a novel mechanism underlying the failure of spontaneous remyelination and neural repair in the pathogenesis of MS.