Emerging Advances of Non-coding RNAs and Competitive Endogenous RNA Regulatory Networks in Asthma

Figures & data

Figure 1. MiRNAs affect the pathogenesis of asthma by regulating immune cells, bronchial epithelial cells and ASMCs. Genetic and environmental factors (e.g., pollen, dust mites, cat hair, cockroaches and other allergens) cause the interaction of airway inflammatory cells (Th2 cells, eosinophils, mast cells, neutrophils, and macrophages), cytokines (e.g., IL-4, IL-5, and IL-13) and inflammatory mediators, ultimately leading to increased airway eosinophilia, mucus overproduction, airway remodeling, airway wall vasodilation, plasma exudation and airway epithelial cell exfoliation and fibrosis. Different miRNAs have different effects on the above processes. The yellow boxes in the picture show typical miRNAs that function in asthma, which correspond to the cells they act on through red arrows. MiRNAs, microRNAs; ASMCs, airway smooth muscle cells

Figure 2. Most IncRNAs and circRNAs are involved in the pathogenesis of asthma through the lncRNA-miRNA-mRNA axis and circRNA-miRNA-mRNA axis, respectively. MiRNAs act as hub nodes in these axis. Different lncRNAs and circRNAs regulate different miRNAs through the sponge effect, and then inhibit mRNA

Figure 3. Schematic expression of regulation by ceRNAs during asthma. Pre-miRNA is generated in the nucleus and transfer to cytoplasm via exportin5. LncRNAs (green) and circRNAs (Orange circle) can influence miRNAs (blue) through the sponge effect in the cytoplasm in asthma. As the picture shows, the overexpression of lncRNA-MEG3 could competitively sponge miR-17 in asthma to regulate the expression of RORγt and ultimately affect the balance of Treg/Th17. Overexpressed circHIPK3 could sponge miR-326 in the cytoplasm, and then promote proliferation, migration and down-regulate the apoptosis in ASMCs by acting on STIM1

Table 1. The role of miRNAs in the pathogenesis of asthma

MiRNA	Unusual expression	Targets	Function	References
Immune cells
Th2 cells
miR-155	Up	CTLA-4	Enhances the secretion of IL-4, -5, -13, -17a; enhances mucus secretion; stimulates T-cell activation and proliferative response	[20,27]
miR-1	Down	-	Inhibits the secretion of IL-4, -5, -8, TNF-α; regulates Th1/Th2 balance	[25]
miR-21	Up	IL-12p35 3ʹUTR	Modulates Th1/Th2 polarization	[31]
miR-3162-3p	Up	β-catenin	Enhances bronchial hyperresponsiveness and airway inflammation; regulates Th1/Th2 balance	[34]
miR-1165-3p	Up	IL-13,PPM1A	Inhibits bronchial hyperresponsiveness, airway inflammation, and differentiation of T cells toward Th2	[35]
miR-200a /200b	Down	ORMDL3	Inhibits the secretion of TNF-α, IL-4, -5, -13, and -1β	[36]
Eosinophils
miR-30a-3p	Down	CCR3	Inhibits the secretion of specific IgE, eotaxin-1, IL-5, and IL-4	[39]
miR-218-5p	Down	CTNND2	Inhibits bronchial hyperresponsiveness, eosinophilic airway inflammation, and the expression of CCL26	[41]
miR-135b	Down	CXCL12	Inhibits the immune response of Th17 cells, goblet cell proliferation, and bronchial hyperresponsiveness; reduces the number of eosinophils and lymphocytes	[42]
miR-135a	Down	The STAT family	Inhibits bronchial hyperresponsiveness and lung pathological changes; reduces the secretion of TNF-α, IL-6, IL-5, and Eotaxin	[43]
Mast cells
miR-221	Up	P27KIP1; PTEN and the p38/NF-κB pathway	Reduces the permeability of inflammatory cells, regulates the cell cycle of mast cells, and promotes their proliferation; increases the secretion of IL-4 and promotes the differentiation of Th cells into Th2 cells	[44–46]
miRNA-142-3p	Up	LPP	Enhances FceRI-mediated degranulation and rescues the reduction of degranulation	[47]
miRNA-126	Up	DNMT1	Increases the number of mast cells	[48]
Neutrophils
miR-629-3p	Up	IL-8 mRNA	Increases the levels of IL-1β and IL-8 protein, which is positively correlated with the increase of neutrophils in sputum	[49]
miR-223	Up	NLRP3	Inhibits the airway inflammation, NLRP3 level and IL-1β release	[51]
Macrophages
miR-142-5p	Up	SOCS1	Modulates the M2 polarization and profibrotic activities	[55]
miR-130a-3p	Down	Proliferator-activated receptor γ	Modulates the M2 polarization and profibrotic activities	[55]
Bronchial smooth muscle cells
miR-26a	Up	GSK-3β	Promotes ASMCs hypertrophy	[57]
miR-378	Up	The genes related to ErbB, RAS, MAPK and calcium signaling pathway	Promotes ASMCs proliferation and apoptosis resistance	[59]
miR-19a	Up	PTEN	Inhibits ASMCs proliferation and migration	[60]
miR-943-3p	Up	SFRP4	Increases the number of macrophages, eosinophils, lymphocytes, and neutrophils, increases the expression of collagen, β-catenin, and c-Myc in lung tissue, and promotes subepithelial fibrosis and ASMCs proliferation	[61]
miR-142	Down	The genes related to EGFR signaling pathway	Inhibits the proliferation of ASMCs and promotes their apoptosis	[62]
miR-204-5p	Down	SIX1	Inhibits ASMCs proliferation and extracellular matrix production	[63]
Bronchial epithelial cells
miR-744	Down	TGF-β1	Inhibits bronchial epithelial cell proliferation	[119]
miR-141	Up	CLCA1	Stimulates IL-13-induced goblet cell metaplasia, promotes airway remodeling and pathological airway mucus production	[67]
miR-146a	Up	IRAK1, TRAF6, FOXO3, PDE7A	Promotes pulmonary mucin deposition, airway remodeling, IgE synthesis, and eosinophilic inflammation	[68,69]
miR-210	Down	FOXP3	Involves in the polarization of Th2 cells	[72]
miR-34a	Down	The genes related to Wnt signaling pathway	Involves in the polarization of Th2 cells	[72]

Table 2. Function of lncRNAs involved in the pathogenesis of asthma

Name of lncRNA	MiRNA sponge	Species/ Cells	Targets	Functions	References
lncRNA MEG3	miR-17	Human/ CD4^+ T cell	RORγt	IL-17 secretion; Treg/ Th17 balance	[78]
lncRNA MALAT1	miR-155	Human/CD4^+ T cell	T-bet, GATA-3	Th1/ Th2 balance	[79]
lncRNA RMRP	miR-155	Mice/ CD4^+ T cell	CCL2	Th1/ Th2 balance	[94]
lncRNA PVT1	miR-203a	Rat/ ASMC	E2F3	The proliferation and migration of ASMCs	[89]
lncRNA PTPRE-AS1	-	Human, mice/Macrophage	PTPRE	M2 macrophage activation	[81]
lnc-BAZ2B	-	Human, mice/Macrophage	BAZ2B	M2 macrophage activation	[82]
lncRNA-AK149641	-	Mice/Mast cell	NF-κB	The inflammatory response in mast cells	[83]
lncTCF7	-	Human/ ASMC	TIMMDC1	The proliferation and migration of ASMCs	[87]
lncRNA MALAT1	miR-150	Human/ ASMC	eIF4E	The proliferation and migration of ASMCs	[90]
lncRNA BCYRN1	miR-150	Rat/ ASMC	-	The proliferation and migration of ASMCs	[120]
lncRNA TUG1	miR-590-5p	Rat/ ASMC	FGF1	The proliferation and migration of ASMCs	[91]
lncRNA TUG1	miR-181b	Rat/ ASMC	HMGB1	The proliferation and migration of ASMCs	[95]
lncRNA 00882	miR-3619-5p	Human/ fetal ASMC	β-catenin	The proliferation of ASMCs	[92]
lncRNA H19	miR-21	Human/ ASMC	PTEN	The proliferation and migration of ASMCs	[96]
lncRNA CASC7	miR-21	Human/ ASMC	PTEN	Regulating PI3K/ AKT signaling pathway; corticosteroid resistance	[99]

Table 3. Function of circRNAs involved in the pathogenesis of asthma

Name of circRNA	MiRNA sponge	Species/ Cells	Targets	Functions	References
circ_0005519	Let-7a-5p	Human/ CD4^+ T cell	IL-13, IL-6	IL-13 and IL-6 expression	[107]
circ_0000723	miR-214	Mice/ CD4^+ T cell	RUNX	Th1/ Th2 balance	[115]
circ_0001359	miR-183-5p	Mice/ macrophage	FoxO1	M2 macrophage activation	[116]
circHIPK3	miR-326	Human/ ASMC	STIM1	The proliferation, migration and apoptosis in ASMCs	[117]

Table

ncRNAs:	Non-coding RNAs
miRNAs:	MicroRNAs
lncRNAs:	Long non-coding RNAs
circRNAs:	Circular RNAs
mRNA:	Messenger RNA
ceRNA:	Competing endogenous RNA
ASMCs:	Airway smooth muscle cells
Th2 cells:	T helper 2 cells
IgE:	Immunogloubulin E
MRE:	MiRNA response element
TGF-β:	Transforming growth factor-β
CTLA-4:	Cytotoxic T lymphocyte-associated protein 4
TNF-α:	Tumor necrosis factor-alpha
OVA:	Ovalbumin
PPM1A:	Protein phosphatase, Mg2+/Mn2+-dependent 1A
ORMDL3:	Orosomucoid 1-like 3
BALF:	Bronchoalveolar lavage fluid
CCR3:	CC chemokine receptor 3
IgE:	Immunoglobulin E
Eotaxin-1:	Eosinophil chemokine-1
SELP:	P-selectin
TSLP:	Thymic stromal lymphopoietin
NF-κB:	nuclear factor-kappa
BTLRs:	Toll-like receptors
IFN-g:	Interferon gamma
GSK-3β:	Glycogen synthase kinase-3β
KLF4:	Krüppel-like factor 4
SFRP4:	Secreted frizzled-related proteins4
Wnt:	Wingless/Integrase-1
EGFR:	Epidermal growth factor receptor
ATG5:	Autophagy-associated protein 5
NHBE:	Normal human bronchial epithelial
LPS:	Lipopolysaccharide
LncRNA GAS5:	LncRNA growth arrest-specificl 5
RMRP:	RNA component of mitochondrial RNA processing endoribonuclease
CCL2:	C-C motif ligand 2
PDGF-BB:	Platelet-derived growth factor-BB
IPSC:	Induced pluripotent stem cell
MSCs:	Mesenchymal stem cells
DUSP6:	Dual-specificity phosphatase 6
CSE:	CS extract
ICF:	Inducible costimulatory factors
VEGF:	Vascular endothelial growth factor
ADSCs:	Adipose-derived stem cells
STIM1:	Stromal interaction molecule 1

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