The lncRNA H19/miR-766-3p/S1PR3 Axis Contributes to the Hyperproliferation of Keratinocytes and Skin Inflammation in Psoriasis via the AKT/mTOR Pathway

Abstract

Background. The pathogenesis of long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) are well studied in psoriasis. However, little is known about how specific lncRNAs and miRNAs affect the mechanism of psoriasis development and which pathways are involved. Objectives. To explore the role of the lncRNA H19/miR-766-3p/S1PR3 axis in psoriasis. Methods. miRNA and lncRNA microarrays were performed using IL-22-induced HaCaT cells and psoriatic lesions, respectively. Fluorescence in situ hybridization and quantitative reverse-transcriptase polymerase chain reaction were used to detect the expression of miR-766-3p and lncRNA H19. Luciferase reporter assays were used to identify miR-766-3p/lncRNA H19 and miR-766-3p/S1PR3 combinations. CCK-8 and ELISA were performed to evaluate the proliferation of keratinocytes and the secretion of pro-inflammatory cytokines. Western blot analysis was used to detect the expression of S1PR3 and its downstream effector proteins. Results. MiR-766-3p was upregulated in both HaCaT cells treated with the psoriasis-related cytokine pool (IL-17A, IL-22, IL-1 alpha, oncostatin M, and TNF-alpha) and tissues. Overexpression of miR-766-3p promoted keratinocyte proliferation and IL-17A and IL-22 secretion. LncRNA H19 and S1PR3 were demonstrably combined with miR-766-3p by luciferase reporter assay. lncRNA H19 repressed proliferation and inflammation, which were reduced by the miR-766-3p. AKT/mTOR pathway effected proliferation and inflammation by the lncRNA H19/miR-766-3p/S1PR3 axis. Conclusions. We established that downregulation of lncRNA H19 promoted the proliferation of keratinocytes and skin inflammation by up-regulating miR-766-3p expression levels and inhibiting activation of S1PR3 through the AKT/mTOR pathway in psoriasis.

Circular RNA protein tyrosine kinase 2 aggravates pyroptosis and inflammation in septic lung tissue by promoting microRNA-766/eukaryotic initiation factor 5A axis-mediated ATP efflux

“…This study identified a potential downstream miRNA (miR-766) of circPTK2 and found that miR-766 was down-expressed in both models of septic ALI, but circPTK2 depletion restored miR-766 levels. miR-766 has been recognized to suppress skin inflammation 35 and attenuate ischemia/perfusion injury-induced cellular inflammation and apoptosis 36 . The paper demonstrated that miR-766 overexpression mitigated the effects of circPTK2 overexpression on cytotoxicity, eATP levels, inflammation, and pyroptosis.…”

Implications of LncRNAs and CircRNAs in psoriasis: a review

“… [ 49 ] LINC00941 Down keratinocyte Inhibits early keratinocytes differentiation [ 50 ] H19 Down Skin As a sponge for miR−766-3p, upregulates S1PR3 levels and regulates psoriatic keratinocyte proliferation and skin inflammation via the AKT/mTOR pathway. [ 51 ] MEG3 Down Skin/HaCaT Blocked regulation of inflammation and autophagy in keratinocytes by TNF-α through the PI3K/AKT/mTOR signaling pathway. [ 52 ] LncRNA-AL162231.4 Down Skin - [ 35 ] ST7OT Down Skin - [ 33 ] LOC285194 Down Skin - [ 33 ] Car Intergenic 10 Down Skin - [ 33 ] NONHSAT044111 Down Skin - [ 48 ] Note: nuclear factor-κB (NF-κB); interleukin enhancer binding factor 2 (ILF2); signal transducer and activator of transcription (STAT); Janus kinase (JAK); extracellular regulated kinase (ERK); AKT serine/threonine kinase 1 (AKT); mechanistic target of rapamycin (mTOR); competitive endogenous RNA (ceRNA); Phosphoinositide 3-kinase (PI3K); Sphingosine 1-phosphate receptor 3 (S1PR3).…”

Sphingosine 1-Phosphate Signaling at the Skin Barrier Interface

“…Furthermore, S1PR2 expression is upregulated in Staphylococcus-aureus-stimulated keratinocytes, and S1PR2 is involved in the formation of skin barrier structures, such as filaggrin, claudin, occludin, and corneodesmosin [ 13 , 14 ]. Moreover, S1PR3 has recently been reported to contribute to the upregulation of IL-17A and IL-22 secretion via the AKT/mTOR pathway [ 53 ] ( Figure 3 ).…”

“…S1PR3 is also related to the mechanism of psoriasis. He et al [ 53 ] reported S1PR3 axis contributes to the hyperproliferation of keratinocytes and skin inflammation in psoriasis via the AKT/mTOR pathway. For S1PR4, Schuster et al [ 72 ] reported that imiquimod-induced psoriatic skin lesions created in S1pr4-deficient mice reduce the severity of psoriasiform dermatitis, decrease CCL2, IL-6, and CXCL1, and reduce infiltrating monocytes and granulocytes.…”