Detrimental Role of miRNA-144-3p in Intracerebral Hemorrhage Induced Secondary Brain Injury is Mediated by Formyl Peptide Receptor 2 Downregulation Both In Vivo and In Vitro

Abstract

Although microRNA-144-3p (miRNA-144-3p) has been shown to suppress tumor proliferation and invasion, its function in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI) remains unclear. Thus, this study was designed to investigate the role of miRNA-144-3p in ICH. To accomplish this, we used adult male Sprague-Dawley rats to establish an in vivo ICH model by injecting autologous blood, while cultured primary rat cortical neurons were exposed to oxyhemoglobin (OxyHb) to mimic ICH in vitro. To examine the role of miRNA-144-3p in ICH-induced SBI, we used an miRNA-144-3p mimic and inhibitor both in vivo and in vitro. Following ICH induction, we found miRNA-144-3p expression to increase. Additionally, we predicted the formyl peptide receptor 2 (FPR2) to be a potential miRNA-144-3p target, which we validated experimentally, with FPR2 expression downregulated when miRNA-144-3p was upregulated. Furthermore, elevated miRNA-144-3p levels aggravated brain edema and neurobehavioral disorders and induced neuronal apoptosis via the downregulation of FPR2 both in vivo and in vitro. We suspected that these beneficial effects provided by FPR2 were associated with the PI3K/AKT pathway. We validated this finding by overexpressing FPR2 while inhibiting PI3K/AKT in vitro and in vivo. In conclusion, miRNA-144-3p aggravated ICH-induced SBI by targeting and downregulating FPR2, thereby contributing to neurological dysfunction and neural apoptosis via PI3K/AKT pathway activation. These findings suggest that inhibiting miRNA-144-3p may offer an effective approach to attenuating brain damage incurred after ICH and a potential therapy to improve ICH-induced SBI.

Functions of resolvin D1-ALX/FPR2 receptor interaction in the hemoglobin-induced microglial inflammatory response and neuronal injury

“…We confirmed that RvD1 had a direct protective effect on primary neurons, which was primary reflected in the improvements in cell viability, inhibition of the production of oxidative stress products, the avoidance of synaptic injury and a reduction in cell death induced by Hb. These results were consistent with those of previous studies [50,53,54]. For example, Peritore et al observed that ALX/FPR2 gene knockout significantly increased the apoptosis of brain neurons in a depression model [50].…”

“…However, the results of some other relevant studies might provide some indications. For instance, Fan et al showed that RvD1 functioned through the PI3K-Akt-caspase-3 pathway in rats with cerebral hemorrhage in vivo and neuronal Hb stimulation in vitro [54]. However, there are few relevant results for other signaling pathways, which need further study in future.…”

ANXA1 directs Schwann cells proliferation and migration to accelerate nerve regeneration through the FPR2/AMPK pathway

“…Formyl peptide receptor 2 (FPR2), a classical chemoattractant receptor of G-protein-coupled receptors, is reported to be involved in cell proliferation and migration in some diseases. 12 A recent study showed that FPR2 had a robust effect on attenuating brain damage and promoting nerve regeneration, 13 and it has been reported that formyl peptide receptors (FPR) enhance the migration and differentiation of rat neural stem cells. 14 The biological effects of ANXA1 are mediated through FPRs.…”

MicroRNA-126-3p Attenuates Intracerebral Hemorrhage-Induced Blood-Brain Barrier Disruption by Regulating VCAM-1 Expression

“…In addition to their diagnostic uses, miRNA could also be used in the treatment of ICH (Jeyaseelan et al, 2007). The over-expression of miR-144-3p aggravates neurological injury after ICH through neuronal apoptosis by the PI3K/AKT pathway (Fan et al, 2018). Moreover, miR-23a-3p has been reported to promote edema formation after ICH via ZO-1 (Hu et al, 2018).…”