MiR-193b-3p–ERBB4 axis regulates psoriasis pathogenesis via modulating cellular proliferation and inflammatory-mediator production of keratinocytes

Abstract

Psoriasis is an auto-inflammatory skin disease characterized by abnormal activation of epidermal keratinocytes, aberrant neovascularization, and dysregulation of immune cells. MicroRNAs are small non-coding RNAs that mainly function in the post-transcriptional regulation of gene expression. Recently, accumulating evidence has demonstrated that expression of microRNAs is dysregulated in psoriasis patients and microRNAs play key roles in psoriasis pathogenesis. Downregulation of miR-193b-3p has been identified to be associated with psoriasis development. However, the precise functions and action mechanisms of miR-193b-3p in psoriasis pathogenesis remain unclear. In this study, we confirmed the downregulation of miR-193b-3p in psoriasis patients, psoriasis-like inflammatory cellular models, and an imiquimod (IMQ) -induced mouse model. A negative correlation was found between miR-193b-3p level and patient Psoriasis Area and Severity Index (PASI) score. Furthermore, miR-193b-3p suppressed proliferation, inflammatory-factor secretion, and the STAT3 and NF-κB signaling pathways in keratinocytes. Importantly, intradermal injection of agomiR-193b-3p blocked, whereas antagomiR-193b-3p augmented, the psoriasis-like inflammation in the IMQ-induced mouse model. Bioinformatics analysis and the dual-luciferase reporter assay showed that miR-193b-3p targets ERBB4 3ʹ untranslated region (UTR). In addition, ERBB4 induced proliferation, inflammatory-factor production, and the STAT3 and NF-κB pathways in keratinocytes. Most importantly, forced expression of ERBB4 could attenuate the effects of miR-193b-3p in keratinocytes, indicating that miR-193b-3p inhibits keratinocyte activation by directly targeting ERBB4. In conclusion, our findings demonstrated that the miR-193b-3p–ERBB4 axis underlies the hyperproliferation and aberrant inflammatory-factor secretion of psoriatic keratinocytes, providing a novel, microRNA-related causal mechanism and a potential therapeutic target in psoriasis.

Sp1‐mediated miR‐193b suppresses atopic dermatitis by regulating HMGB1

“…25 miR-193b overexpression suppressed inflammatory factor secretion in activated keratinocytes. 11 Considering the role of miR-193b in regulating keratinocyte inflammatory response and its differential expression in AD, we further investigated its specific role in AD. In this study, we observed low miR-193b expression levels in the skin tissues of AD patients and TNF-α/IFN-γ-treated HaCaT cells, a commonly used inflamed keratinocyte model.…”

“…miR‐193b is involved in the progression of inflammatory skin diseases. Huang et al revealed that the miR‐193b‐3p level was inversely correlated with disease severity in psoriasis patients, and its upregulation remarkably repressed keratinocyte proliferation and inflammatory cytokine secretion 11 . Although miR‐193b was found to be significantly downregulated in AD, 12 the molecular mechanism underlying miR‐193b‐mediated suppression of AD progression is still unclear.…”

“…Huang et al revealed that the miR-193b-3p level was inversely correlated with disease severity in psoriasis patients, and its upregulation remarkably repressed keratinocyte proliferation and inflammatory cytokine secretion. 11 Although miR-193b was found to be significantly downregulated in AD, 12 the molecular mechanism underlying miR-193b-mediated suppression of AD progression is still unclear. Nuclear transcription factor (TF) specificity protein 1 (Sp1) is involved in several cellular functions, 13 including inflammatory injury and antiviral response.…”

Anti-Inflammatory microRNAs for Treating Inflammatory Skin Diseases

“…miR-193b-3p is another anti-inflammatory miRNA used to achieve the amelioration of psoriasis. Huang et al [ 58 ] transfected miR-193b-3p mimics in HaCaT and observed suppressed proliferation and NF-κB/STAT3 signaling. The bioinformatic analysis and dual-luciferase reporter assay indicated that miR-193b-3p could diminish keratinocyte activation by directly targeting the Erb-B2 receptor tyrosine kinase 4 (ERBB4).…”

The Desmosome-Keratin Scaffold Integrates ErbB Family and Mechanical Signaling to Polarize Epidermal Structure and Function

“…Properly tuned ErbB signaling is critical for normal skin homeostasis. While elevated ErbB signaling is associated with chronic inflammatory disorders, EGFR helps mount innate immune responses and epidermal loss of EGFR or EGFR receptor inhibitors used in cancer treatment elicit adverse inflammatory rashes ( Pastore et al, 2008 ; Lichtenberger et al, 2013 ; Mascia et al, 2013 ; Huang et al, 2021 ). Given the role of cadherin-cytoskeletal networks in controlling ErbB signaling, this raises the question of whether altered signaling resulting from a damaged desmosome-IF network contributes to an immune response.…”