Increased expression of miR142 and miR155 in glial and immune cells after traumatic brain injury may contribute to neuroinflammation via astrocyte activation.

Anatoly Korotkov,Mette Heiskanen,Eleonora Aronica,Niina Vuokila,Shalini Das Gupta,Jasper J Anink,Erwin A Van Vliet,James D Mills,Noora Puhakka,Inge Huitinga,Diede W M Broekaart,Asla Pitkänen,Jackelien Van Scheppingen,Jenni Karttunen

doi:10.1111/bpa.12865

Abstract

Traumatic brain injury (TBI) is associated with the pathological activation of immune‐competent cells in the brain, such as astrocytes, microglia and infiltrating immune blood cells, resulting in chronic inflammation and gliosis. This may contribute to the secondary injury after TBI, thus understanding of these processes is crucial for the development of effective treatments of post‐traumatic pathologies. MicroRNAs (miRNAs, miRs) are small noncoding RNAs, functioning as posttranscriptional regulators of gene expression. The increased expression of inflammation‐associated microRNAs miR155 and miR142 has been reported after TBI in rats. However, expression of these miRNAs in the human brain post‐TBI is not studied and their functions are not well understood. Moreover, circulating miR155 and miR142 are candidate biomarkers. Therefore, we characterized miR142 and miR155 expression in the perilesional cortex and plasma of rats that underwent lateral fluid‐percussion injury, a model for TBI and in the human perilesional cortex post‐TBI. We demonstrated higher miR155 and miR142 expression in the perilesional cortex of rats 2 weeks post‐TBI. In plasma, miR155 was associated with proteins and miR142 with extracellular vesicles, however their expression did not change. In the human perilesional cortex miR155 was most prominently expressed by activated astrocytes, whereas miR142 was expressed predominantly by microglia, macrophages and lymphocytes. Pro‐inflammatory medium from macrophage‐like cells stimulated miR155 expression in astrocytes and overexpression of miR142 in these cells further potentiated a pro‐inflammatory state of activated astrocytes. We conclude that miR155 and miR142 promote brain inflammation via astrocyte activation and may be involved in the secondary brain injury after TBI.

Highlights

Traumatic brain injury (TBI) is a major cause of death and disability in humans, which is estimated to affect more than 50 million people worldwide every year [12,32]
Numerous molecular changes following the primary brain injury contribute to the secondary brain injury, which includes brain inflammation, reactive gliosis, blood-brain barrier (BBB) dysfunction, axonal injury, progressive neuronal loss and remodeling of the extracellular matrix (ECM) [36,41,45,53]
We investigated the expression of miR155 in the perilesional cortex of rats 2 weeks post-TBI in the lateral fluid percussion injury (FPI) model

Summary

Introduction

Traumatic brain injury (TBI) is a major cause of death and disability in humans, which is estimated to affect more than 50 million people worldwide every year [12,32]. It involves a number of pathological alterations as a result of external damage to the brain [36,40]. Sustained brain inflammation leads to chronic activation of glial cells and infiltration of neutrophils, lymphocytes and macrophages in the brain parenchyma [19,49] This negatively affects the neuronal survival and promotes BBB dysfunction, further contributing to the secondary injury post-TBI. A better understanding of the molecular and cellular alterations involved in brain inflammation is crucial for the development of effective and adequate management of post-TBI neuropathology

Methods

Results

Discussion

Conclusion