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

Abstract

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.

Photobiomodulation Promotes Repair Following Spinal Cord Injury by Regulating the Transformation of A1/A2 Reactive Astrocytes

“…Subsequently, A1-specific transcript levels were gradually upregulated and reached a peak at 7 dpi due to the inflammatory response, which begins to cause most of the secondary damage ( Zamanian et al, 2012 ; Liddelow and Barres, 2017 ). However, when A1 astrocytes are activated after SCI is controversial, as Qian et al (2019) and Jiang et al (2020) reported that A1 astrocytes can be observed only at 28 dpi, but Zhang Y. et al (2021) claimed that naïve astrocytes transformed into A1 astrocytes at 3 dpi. These differences may have been due to the unclear definition of A1/A2 astrocyte activation, which was first described ( Liddelow et al, 2017 ) in cell culture conditions.…”

Silencing of miR ‐132‐3p protects against neuronal injury following status epilepticus by inhibiting IL ‐1β‐induced reactive astrocyte ( A1 ) polarization

“…Astrogliosis is an important pathological feature of MTLE, where astrocytes undergo molecular, morphological, and functional changes in both acute and progressive pathological conditions, which are referred to as astrocyte reactivity. 5,36,37 The impact of astrocyte reactivity on disease outcomes is controversial, and there is substantial evidence that it both impedes and supports CNS recovery, 11,18,38,39 and this "reactive profile" can last from hours to days or even decades. Reactive astrocytes appear with various polarization states in different CNS diseases.…”

A Novel Progress: Glial Cells and Inflammatory Pain

“… Therefore, inhibition of the A1 astrocyte transformation can effectively inhibit the inflammatory response. Studies have shown that inhibiting microRNA-21a-5p can up-regulate the ciliary neurotrophic factor (CNTF)/STAT3/NF-κB repressing factor (Nkrf) pathway and reduce the polarization of A1 astrocytes, thereby reducing the inflammatory response . HSF1 regulates NF-κB activity by inhibiting the nuclear binding activity of NF-κB or decreasing the degradation of IκB protein.…”