miR-24 targets SARS-CoV-2 co-factor Neuropilin-1 in human brain microvascular endothelial cells: Insights for COVID-19 neurological manifestations

Abstract

Neuropilin-1 is a transmembrane glycoprotein that has been implicated in several processes including angiogenesis and immunity. Recent evidence has also shown that it is implied in the cellular internalization of the severe acute respiratory syndrome coronavirus (SARS-CoV-2), which causes the coronavirus disease 2019 (COVID-19). We hypothesized that specific microRNAs can target Neuropilin-1. By combining bioinformatic and functional approaches, we identified miR-24 as a regulator of Neuropilin-1 transcription. Since Neuropilin-1 has been shown to play a key role in the endothelium-mediated regulation of the blood-brain barrier, we validated miR-24 as a functional modulator of Neuropilin-1 in human brain microvascular endothelial cells (hBMECs), which are the most suitable cell line for an in vitro blood–brain barrier model.

The Role of Neuropilin-1 (NRP-1) in SARS-CoV-2 Infection: Review

“…Due to the fact that NRP-1 is involved in endothelial-dependent immune responses in the human brain, Mone et al attempted to identify microRNAs (miRNAs) that specifically target NRP-1 in brain microvascular endothelial cells representing the blood-brain barrier. Using Targetscan 7.2, the authors identified hsa-miR-24-3p (miR-24), which is probably a modulator of neuropilin-1 mRNA expression [32]. Therefore, miR-24 has been indicated as a potentially therapeutic target focused on the reduction in endothelium-dependent inflammation.…”

“…Therefore, miR-24 has been indicated as a potentially therapeutic target focused on the reduction in endothelium-dependent inflammation. Additionally, it has been found that miR-24 decreases the blood-brain barrier permeability in response to vascular endothelial growth factor (VEGF), which has been indicated as one of the most studied ligands of NRP-1 [32]. Moreover, it has been revealed that VEGF-A sensitizes nociceptor activity which initiates the sensation of pain in the central nervous system [33,34].…”

Endothelial contribution to COVID-19: an update on mechanisms and therapeutic implications

“…Though ECs were not included in the cell line experiments, the scRNA-seq data from human lung and olfactory epithelium emphasized the highest levels of NRP1 in ECs, implying that NRP1 may play a potential role in the reciprocal action between SARS-CoV-2 and endothelium [ 59 ]. In fact, NRP1 is a well-characterized co-receptor of vascular endothelial growth factor (VEGF) in ECs [ 62 , 63 ], its cell surface expression on ECs has been well acknowledged.…”

miRNAs, from Evolutionary Junk to Possible Prognostic Markers and Therapeutic Targets in COVID-19

“…NRP1 is a transmembrane receptor that binds to SARS-CoV-2 proteins, improving the entry of the virus into the CNS by facilitating the fusion of membranes in neuronal tissue. In addition, it induces viral replication, neuronal death, and vWF secretion in endothelial cells, accompanied by angiogenesis and platelet activation, which exacerbates CNS damage and increases the risk of CVD [142][143][144]. Usually, miR-24 is capable of repressing the expression of NRP1; however, a decrease in this miRNA has been shown in COVID-19, which could increase the expression of NRP1 and, along with this, increase the neurological damage caused by the virus entering neuronal cells [142].…”