Abstract
The brain and the immune system interact in complex ways after ischemic stroke, and the long-term effects of immune response associated with stroke remain controversial. As a linkage between innate and adaptive immunity, interleukin-17 A (IL-17 A) secreted from gamma delta (γδ) T cells has detrimental roles in the pathogenesis of acute ischemic stroke. However, to date, the long-term actions of IL-17 A after stroke have not been investigated. Here, we found that IL-17 A showed two distinct peaks of expression in the ischemic hemisphere: the first occurring within 3 days and the second on day 28 after stroke. Our data also showed that astrocyte was the major cellular source of IL-17 A that maintained and augmented subventricular zone (SVZ) neural precursor cells (NPCs) survival, neuronal differentiation, and subsequent synaptogenesis and functional recovery after stroke. IL-17 A also promoted neuronal differentiation in cultured NPCs from the ischemic SVZ. Furthermore, our in vitro data revealed that in primary astrocyte cultures activated astrocytes released IL-17 A via p38 mitogen-activated protein kinase (MAPK). Culture media from reactive astrocytes increased neuronal differentiation of NSCs in vitro. Blockade of IL-17 A with neutralizing antibody prevented this effect. In addition, after screening for multiple signaling pathways, we revealed that the p38 MAPK/calpain 1 signaling pathway was involved in IL-17 A-mediated neurogenesis in vivo and in vitro. Thus, our results reveal a previously uncharacterized property of astrocytic IL-17 A in the maintenance and augment of survival and neuronal differentiation of NPCs, and subsequent synaptogenesis and spontaneous recovery after ischemic stroke.
Highlights
The elements of the immune system are shown to be intimately involved in all stages of ischemic stroke, from the early damaging events to the late regenerative processes underlying post-ischemic tissue repair, which determinates the fate of the stroke and the survival of stroke patients.[5]
We showed that interleukin-17 A (IL-17 A) from reactive astrocytes maintained and augmented the survival and neuronal differentiation of neural precursor cells (NPCs) in the subventricular zone (SVZ), and subsequent synaptogenesis and spontaneous recovery through the p38 mitogen-activated protein kinase (MAPK)/calpain 1 signaling pathway
IL-17 A-positive cells were significantly increased at 7 and 14 days post-ischemia (d.p.i.) in the ischemic dentate gyrus (DG), but not at 21 or 28 d.p.i. (Figure 1c); whereas IL-17 A-positive cells were significantly increased at all time points in the SVZ (Figure 1e)
Summary
The elements of the immune system are shown to be intimately involved in all stages of ischemic stroke, from the early damaging events to the late regenerative processes underlying post-ischemic tissue repair, which determinates the fate of the stroke and the survival of stroke patients.[5]. The early activation of innate immunity and the release of immune cytokines exert detrimental effects in acute phase of stroke,[6,7] which are not related to adaptive immunity.[8] the adaptive immunity to brain antigens occurs in the later phases and may have important roles in neurovascular remodeling and functional recovery during stroke recovery.[5] Among various immune cytokines secreted by immune cells, we focused on interleukin-17 A (IL-17 A) owing to three recently proposed ideas. Our findings reveal a previously unsuspected role for IL-17 A in the survival and neuronal differentiation of NPCs, and subsequent synaptogenesis and long-term functional outcome after ischemic stroke
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