Astrocytes are the most populous glial cells in the central nervous system (CNS). They are essential to CNS physiology and play important roles in the maintenance of homeostasis, development of synaptic plasticity, and neuroprotection. Nevertheless, under the influence of certain factors, astrocytes may also exert detrimental effects through a process of reactive astrogliosis. Previous studies have shown that astrocytes have more than one type of polarization. Two types have been extensively researched. One is a damaging change that occurs under inflammation and has been termed A1 astrocyte, while the other is a restorative change that occurs under ischemic induction and was termed A2 astrocyte. Researchers are now increasingly paying attention to the role of astrocytes in spinal cord injury (SCI), degenerative diseases, chronic pain, neurological tumors, and other CNS disorders. In this review, we discuss (a) the characteristics of polarized astrocytes, (b) the relationship between astrocyte polarization and SCI, and (c) new implications of reactive astrogliosis for future SCI therapies.

Reactive astrocytes are implicated in traumatic spinal cord injury (TSCI). Interestingly, naïve astrocytes can easily transform into neurotoxic reactive astrocytes (A1s) with inflammatory stimulation. Previous studies demonstrated that microRNA(miR)-21a-5p was up-regulated in spinal cord tissue after TSCI; however, it is not clear whether this affected reactive astrocyte polarization. Here, we aim to detect the effects of miR-21a-5p on the induction of A1 formation and the underlying mechanisms. Our study found that the expression of miR-21a-5p was significantly increased while that of Cntfr α was decreased, since naïve astrocytes transformed into A1s 3 days post-TSCI; the binding site between miR-21a-5p and Cntfr α was further confirmed in astrocytes. After treatment with CNTF, the levels of A1 markers decreased while that of A2 increased. The expression of A1 markers significantly decreased with the downregulation of miR-21a-5p, while Cntfr α siRNA treatment caused the opposite both in vitro and in vivo . To summarize, miR-21a-5p/Cntfr α promotes A1 induction and might enhance the inflammatory process of TSCI; furthermore, we identified, for the first time, the effect and potential mechanism by which CNTF inhibits naïve astrocytes transformation into A1s. Collectively, our findings demonstrate that targeting miR-21a-5p represents a prospective therapy for promoting the recovery of TSCI.

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Background Reactive astrocytes play an important role in Traumatic Spinal Cord Injury (TSCI). Interestingly, naive astrocytes can easily transform into neurotoxic reactive astrocytes(A1s) when inflammatory stimulation occurs. Previous researches have reported that miR-21a-5p is involved in the regulation of various stages of Spinal Cord Injury (SCI). However, it is not clear whether miR-21a-5p affected the polarization of reactive astrocytes. The purpose of our study was to detect the effects and mechanism of miR-21a-5p in the induction of neurotoxic reactive astrocytes (A1s) formation. Methods Gene chip assay and qRT-PCR were used to detect the expression of Cntfr α in TSCI models or sham operation. Bioinformatics analysis was used to speculate the potential targeting of miR-21a-5p, which was further confirmed by qRT-PCR, western blotting, a dual-luciferase reporter assay, and RNA pulldown assay. In vivo, the TSCI model was performed by a 68099Ⅱ precision percussion device, and the A1s phenotype was identified by immunofluorescence staining. In vitro, A1s were induced by IL-1 α, TNF-α, and C1q. A1s and neuroprotective reactive astrocytes (A2s) markers were confirmed by qRT-PCR, western blotting, and immunofluorescence. ChIP assay was used to explore the targeting gene of STAT3, the downstream of Cntfr α. Results The expression of miR-21a-5p was significantly increased while Cntfr α was decreased since naive astrocytes transformed into A1s after 3 days post-TSCI. In addition, the mRNA and protein of Cntfr α were decreased while miR-21a-5p was overexpressed. The binding site between miR-21a-5p and Cntfr α was further confirmed by the dual-luciferase reporter and RNA pulldown assay. We also discovered that A1s markers were decreased while markers of A2s were increased with the pretreatment of CNTF. Chromatin immunoprecipitation (ChIP) assay was used to prove that CNTF inhibited A1s induction by activating the expression of Nkrf via the CNTF/STAT3 pathway. Downregulation of miR-21a-5p enhanced the inhibitory effect of CNTF in A1s in vitro. In vivo, the expression of A1s markers significantly decreased with the treatment of antagomir-21, while Cntfr α siRNA treatment was just the opposite. Conclusion We observed that increased miR-21a-5p down-regulated Cntfr α in A1s induced by TSCI, promoting the inflammatory process. In addition, we also identified the effect and potential mechanism of CNTF, a specific ligand of CNTFR α, on inhibiting naive astrocytes transformed into A1s for the first time. Collectively, our studies demonstrated that targeting miR-21a-5p is a prospective therapy for curing TSCI.