LncRNA, an Emerging Approach for Neurological Diseases Treatment by Regulating Microglia Polarization

Abstract

Neurological disorders cause untold human disability and death each year. For most neurological disorders, the efficacy of their primary treatment strategies remains suboptimal. Microglia are associated with the development and progression of multiple neurological disorders. Targeting the regulation of microglia polarization has emerged as an important therapeutic strategy for neurological disorders. Their pro-inflammatory (M1)/anti-inflammatory (M2) phenotype microglia are closely associated with neuronal apoptosis, synaptic plasticity, blood-brain barrier integrity, resistance to iron death, and astrocyte regulation. LncRNA, a recently extensively studied non-coding transcript of over 200 nucleotides, has shown great value to intervene in microglia polarization. It can often participate in gene regulation of microglia by directly regulating transcription or sponging downstream miRNAs, for example. Through proper regulation, microglia can exert neuroprotective effects, reduce neurological damage and improve the prognosis of many neurological diseases. This paper reviews the progress of research linking lncRNAs to microglia polarization and neurological diseases.

Keywords: lncRNA; miRNA; microglia polarization; neuroinflammation; neurological diseases.

FIGURE 1

Regulation mechanism of miRNA on microglia polarization. (1) Signaling pathway of M1 polarization regulated by miRNA. miR-21-5p acts on microglia through releasing pro-inflammatory substances, while miR-214-5p suppress the expression of CXCR5 and other pro-inflammatory substances like IL-6, IL-8, TNF-α. NF-κB is thought to be a common pro-inflammatory signal pathway. miR-409-3p can downregulate Nr4a2 (a suppressor of NF-κB) to activate microglia. MiR-138 may activate the TLR7 to promote NF-κB. (2) Signaling pathway of M2 polarization regulated by miRNA. The exosomes containing miR-223-3p, miR-30d-5p, or miR-126 may suppress the synthesis of inflammatory factors to inhibit the activation of microglia. There is some genetic expression may influence the polarization of microglia.miR-146a-5p may downregulate IRK1 and NFT5 to inhibit the activation of microglia. MiR-124-3p may suppress the expression of MYH9.miR-26b-5p may suppress the expression of CH25H. miR-873-5p may suppress the NF-κB signaling pathway, which is very common in inflammation. All these three miRNA can inhibit microglia polarization. TLR4 signal pathway is a common way to promote inflammation, while the inhibition of it can suppress the process. Exosomes of miR-93 may suppress the NF-κB signaling pathway through downregulating TLR4 expression. Similar exosomes of miR-216a-5p may activates the PI3K/AKT signaling pathway and the expression of NF-κB through the downregulation of TLR4 to promote the M2 microglia. IKK is a stimulators of NF-κB. miR-199b may downregulate IKK to inhibit NF-κB and microglia activation.

FIGURE 2

Regulation mechanism of lncRNA/miRNA axis on microglia polarization. It is very common to see that lncRNA can play a role in regulating the microglia through mediating the miRNA, like sponging the miRNA. By sponging the miR-136-5p, HOTAIR may activate M1 phenotype by upregulating AKT2 to upregulate NF-κB. Similarly, by sponging the miRNA, TUG1 may activate the microglia through NF-κB. Meg3 and sponged miR-7a-5p may together upregulate the NLRP3 to promote M1 phenotype. GAS5 may increases the expression of Notch1 protein signaling through sponging miR-146a-5p to promote M1 polarization in microglia, but this influence can be disrupted by STV-Na to convert to M2. Meanwhile, one of the crucial pathways in switching the polarization of microglia is the activation of STAT family. STAT1 and STAT3 are related to M1 phenotype, while STAT6 is related to M2 phenotype. SNHG15 may promotes STAT1 and its NF-κB expression by sponging miR-302a-3p. H19 may sponge let-7b to promote STAT3 activation, and in some cases, it might activate the M1 phenotype by increasing the HDAC1. However, H19 may also exert a promotion of M2 phenotype by sponging miR-29b-3p. Contrary to M1 phenotype, SNHG4 may promote M2 polarization in microglia and activate the STAT6 by sponging miR-449c-5p. LncRNA may downregulate the expression of miRNA. KCNQ1OT1 promotes M1 polarization in microglia by downregulating miR-873-5p to promote TRAF6 -mediated p38/MAPK pathway. SNHG14 promotes M1 phenotype by suppressing the expression of miR-145-5p on PLA2G4A. lncGm37494 promotes M2 polarization by inhibiting miR-130b-3p to promote the PPARγ pathway.

FIGURE 3

Multiple function of microglia polarization in the central nervous system. Usually, microglia can be activated to M1 phenotype in central system by LPS, IFN-γ, and Aβ, exerting pro-inflammatory effects. And it can be stimulated to M2 phenotype by IL-4 and IL-13, exerting anti-inflammatory effects. NaF and NOX2 may promote the oxidative stress of microglia and its subsequent impact, while it can reversed by enhanced Nrf2. Meanwhile, the substances like Short-chain fatty acids and gut microbiota that are outside the BBB can also activate microglia by crossing the BBB. However, activated M1 microglia can damage the blood-brain barrier by secreting ROS, TNF-α, chemotactic proteins CCL2 and CXCL10. And in some cases, the over-activated microglia may produce cytokines and MMPs that further impair blood-brain barrier function. The integrity of BBB is related to the cellular junctions, in which the claudin-5 is an important factor. And the M2 phenotype of microglia can produce IL-10 and TGF-β1 to stabilize the BBB. Astrocyte-specific GSTM1 may enhance inflammatory responses of activated microglia. And microglia can release inflammatory mediators such as Il-1α, TNF and C1q to convert astrocytes to the neurotoxic A1 phenotype, enhancing the inflammation. Mn toxicity-induced activation of NF-κB signaling in microglia, which can also regulate cytokines and chemokines, promotes the A1 phenotype of astrocytes. NLY01 can prevent the microglia from releasing these mediators and cytokines, thus inhibiting the conversion of astrocyte. Astrocyte can also produce IL-33, which might activate microglia to remodel the extracellular matrix, showing a capability to restrain the synaptic plasticity. M1 microglia can prevent the BDNF from releasing, thus reducing activation and phosphorylation of synaptic TrkB receptors and inhibiting the expression of glutamate transporters and NMDA receptors, ultimately impairs LTP. But in other cases, M2 microglia might produce BDNF to improve it. The fluoxetine can induce apoptosis of activated microglia, while depletion of such activated microglia with PLX3397 reduces neuronal apoptosis. NF-κB is able to promote the activation of microglia and the expression of NLRP3, thus initiating pyroptosis of microglia. But the inhibition of caspase-1 reduces microglia pyroptosis. M1-polarized microglia exhibit higher resistance, whereas M2-polarized microglia exhibit higher sensitivity. But the inhibition of HO-1 may reduce the risk of ferroptosis.