Interleukin-17A regulates ependymal cell proliferation and functional recovery after spinal cord injury in mice

Hisao Miyajima,Toshihide Yamashita,Shogo Tanabe,Takahide Itokazu

doi:10.1038/s41419-021-04064-1

Abstract

Ependymal cells have been suggested to act as neural stem cells and exert beneficial effects after spinal cord injury (SCI). However, the molecular mechanism underlying ependymal cell regulation after SCI remains unknown. To examine the possible effect of IL-17A on ependymal cell proliferation after SCI, we locally administrated IL-17A neutralizing antibody to the injured spinal cord of a contusion SCI mouse model, and revealed that IL-17A neutralization promoted ependymal cell proliferation, which was paralleled by functional recovery and axonal reorganization of both the corticospinal tract and the raphespinal tract. Further, to test whether ependymal cell-specific manipulation of IL-17A signaling is enough to affect the outcomes of SCI, we generated ependymal cell-specific conditional IL-17RA-knockout mice and analyzed their anatomical and functional response to SCI. As a result, conditional knockout of IL-17RA in ependymal cells enhanced both axonal growth and functional recovery, accompanied by an increase in mRNA expression of neurotrophic factors. Thus, Ependymal cells may enhance the regenerative process partially by secreting neurotrophic factors, and IL-17A stimulation negatively regulates this beneficial effect. Molecular manipulation of ependymal cells might be a viable strategy for improving functional recovery.

Highlights

Spinal cord injury (SCI) is a debilitating neurological condition that can lead to severe and permanent deficits in sensorimotor function
These results indicate that IL-17A exerts a suppressive both the corticospinal tract (CST) and the raphespinal tract (RST), which might be the anatomical basis of effect on functional recovery and axonal reorganization by improved motor function
We demonstrated that ependymal cell-specific conditional knockdown of IL-17 receptor A (IL-17RA) is sufficient to improve the functional outcome after SCI with enhanced axonal reorganization, providing evidence that manipulation of ependymal cells is a promising therapeutic strategy after SCI

Summary

INTRODUCTION

Spinal cord injury (SCI) is a debilitating neurological condition that can lead to severe and permanent deficits in sensorimotor function. Recent research sheds light on the beneficial aspects of these processes [1, 10], the local environment in the injured spinal cord is inhospitable for neural recovery and regeneration [11,12,13,14]. Targeting ependymal cells to establish a therapeutic strategy to provide a regenerationpermissive local environment seems promising. By using a contusion SCI mouse model, we showed that local inhibition of IL-17A signaling promotes both anatomical and functional recovery, and this treatment enhances ependymal cell proliferation. Ependymal cell-specific conditional knockdown of IL-17 receptor A (IL-17RA) was shown to be enough to promote anatomical and functional recovery after SCI. There was no clear difference in the number or morphology of astrocytes and microglial cells (Supplementary Fig. 2a–e), the proliferation ability of the cells

RESULTS

Miyajima et al 3

DISCUSSION

MATERIALS AND METHODS

Findings

ETHICS STATEMENT