miR-21a-5p Promotes Inflammation following Traumatic Spinal Cord Injury through Upregulation of Neurotoxic Reactive Astrocyte (A1) Polarization by Inhibiting the CNTF/STAT3/Nkrf Pathway

Reactive astrocytes are implicated in traumatic spinal cord injury (TSCI). Interestingly, nave 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 alpha was decreased, since nave astrocytes transformed into A1s 3 days post-TSCI; the binding site between miR-21a-5p and Cntfr alpha 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 alpha siRNA treatment caused the opposite both in vitro and in vivo. To summarize, miR-21a-5p/Cntfr alpha 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 nave astrocytes transformation into A1s. Collectively, our findings demonstrate that targeting miR-21a-5p represents a prospective therapy for promoting the recovery of TSCI.

Automated summary

Our study found that miR-21a-5p has effects on the induction of A1 astrocytes and revealed the potential mechanism. Additionally, CNTF was shown to inhibit the transformation of naive astrocytes into A1s.