The role of the microRNA-146a/complement factor H/interleukin-1β-mediated inflammatory loop circuit in the perpetuate inflammation of chronic temporal lobe epilepsy.

Tao-Ran Li,Yan-Jie Jia,Rui-Juan Lv,Chao Ma,Wen-Ying Qiu,Qun Wang,Xiao-Qiu Shao

doi:10.1242/dmm.031708

Abstract

ABSTRACTIncreasing evidence indicates that neuroinflammation plays a crucial role in the pathogenesis of temporal lobe epilepsy (TLE). However, it is unclear how the perpetuate inflammation develops. Some recent studies have suggested the possible involvement of microRNA-146a (miR-146a) in the modulation of inflammatory signaling occurring in TLE. To understand how miR-146a modulates inflammatory signaling in TLE, we investigated the role of interleukin-1β (IL-1β), miR-146a and human complement factor H (CFH) in the perpetuate inflammation in rat models of chronic TLE and U251 cells. We found that enhancive miR-146a could upregulate the expression of IL-1β and downregulate the expression of CFH, whereas reductive miR-146a could downregulate the expression of IL-1β and upregulate the expression of CFH, in hippocampi of chronic TLE rat models. Meanwhile, enhancive miR-146a could increase the abnormal wave forms in the chronic TLE rat models. Additionally, enhancive IL-1β could feedback downregulate the expression of CFH, upregulate the expression of miR-146a and increase the abnormal wave forms in chronic TLE rat models. After CFH gene knockdown in U251 cells, enhancive miR-146a did not upregulate the expression of IL-1β. In summary, this study shows that enhancive miR-146a can upregulate the inflammatory factor IL-1β in chronic TLE by downregulating CFH, and that upregulation of IL-1β plays an important feedback-regulating role in the expression of miR-146a and CFH, forming a miR-146a–CFH–IL-1β loop circuit that initiates a cascade of inflammation and then leads to the perpetuate inflammation in TLE. Therefore, modulation of the miR-146a–CFH–IL-1β loop circuit could be a novel therapeutic target for TLE.

Highlights

Epilepsy is a neurological disorder that is characterized by a predisposition to generate seizures associated with neurobiological, psychological, cognitive and linguistic problems (Duncan et al, 2006)
Status epilepticus induced by intrahippocampal kainic acid After microinjecting kainic acid (KA) into the CA3 region of the posterior hippocampus, the behavioral seizures of the rat models were continuously monitored for 24 h with video recording
We investigated whether miR-146a can regulate inflammation by the complement factor H (CFH) pathway, and whether IL-1β can feedback regulate miR-146a and CFH, forming an inflammation loop circuit that leads to the perpetuate inflammation in chronic temporal lobe epilepsy (TLE) rats

Summary

Introduction

Epilepsy is a neurological disorder that is characterized by a predisposition to generate seizures associated with neurobiological, psychological, cognitive and linguistic problems (Duncan et al, 2006). There are 65 million people worldwide with epilepsy (with developing countries accounting for 80% of all cases), producing a heavy health and economic burden (Hirtz et al, 2007; Winkler et al, 2007). World Health Organization (WHO) research has shown that epilepsy accounts for 1% of the global disease burden, which is equivalent to the burden of male lung cancer or female breast cancer patients (Engel, 2008). The anti-epilepsy measures targeting these mechanisms still cannot produce satisfactory effects (Pitkänen and Lukasiuk, 2011). It is estimated that one-third of epilepsy patients will develop drug refractory epilepsy, even with the introduction of some new anti-epileptic drugs over the past two decades (Laxer et al, 2014). The failure of drug treatment might be caused by an incomplete understanding of the pathophysiological mechanism underlying drug refractory epilepsy; it is important to explore this mechanism further

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