miR-21-3p/IL-22 Axes Are Major Drivers of Psoriasis Pathogenesis by Modulating Keratinocytes Proliferation-Survival Balance and Inflammatory Response

Abstract

Psoriasis is a chronic inflammatory skin disease that is mediated by complex crosstalk between immune cells and keratinocytes (KCs). Emerging studies have showed a specific psoriatic microRNAs signature, in which miR-21 is one of the most upregulated and dynamic miRNAs. In this study, we focused our investigations on the passenger miR-21-3p strand, which is poorly studied in skin and in psoriasis pathogenesis. Here, we showed the upregulation of miR-21-3p in an IMQ-induced psoriasiform mouse model. This upregulation was correlated with IL-22 expression and functionality, both in vitro and in vivo, and it occurred via STAT3 and NF-κB signaling. We identified a network of differentially expressed genes involved in abnormal proliferation control and immune regulatory genes implicated in the molecular pathogenesis of psoriasis in response to miR-21-3p overexpression in KCs. These results were confirmed by functional assays that validated the proliferative potential of miR-21-3p. All these findings highlight the importance of miR-21-3p, an underestimated miRNA, in psoriasis and provide novel molecular targets for therapeutic purposes.

miR-21-3p regulates keratinocyte proliferation and apoptosis possibly via regulating Janus kinase/signal transducer and activator of transcription-3 pathway and cytokeratin 17 expression

“…These results suggest that miR-21-3p may play a promoting role in psoriasis, consistent with previous study. 17 The role of miR-21-3p in psoriasis is consistent with the role of miR-21-5p in psoriasis. 21,22 Moreover, miR-21-3p mimics could promote DNA replication and promote the G1 phase of the cell cycle, indicating that miR-21-3p may mediate abnormal changes in HaCaT cell proliferation by regulating the G1 phase of the cell cycle.…”

“…20 Additionally, the miR-21–3p is shown to be a major driver for the pathogenesis of psoriasis. 17 However, its role in psoriasis is emerging. In this study, we found that miR-21-3p mimics promoted the proliferation and inhibited apoptosis of HaCaT cells, while miR-21-3p inhibitor showed the opposite effect.…”

“…miR-21-5p has been confirmed by many studies to promote the occurrence and development of psoriasis vulgaris. 16 The role of miR-21-3p in psoriasis is emerging 17…”

“…miR-21-5p has been confirmed by many studies to promote the occurrence and development of psoriasis vulgaris. 16 The role of miR-21-3p in psoriasis is emerging 17 Herein, we investigated the effect of miR-21-3p on the proliferation, cell cycle and apoptosis of HaCaT cells and the underlying mechanism involving JAK/STAT3 pathway. Our findings may provide new targets for the diagnosis and treatment of psoriasis.…”

Targeting TGF-β1/miR-21 Pathway in Keratinocytes Reveals Protective Effects of Silymarin on Imiquimod-Induced Psoriasis Mouse Model

“…(2014) showed that impaired activation of IL-6/signal transducer and activator of transcription 3 pathway in epidermal lesions of patients with psoriasis could trigger the upregulation of miR-21-5p, which in turn leads to activation of TACE/ADAM17. In line with these studies, we recently identified IL-22 as a potent inducer of miR-21-5p expression ( Abdallah et al., 2021 ) and showed that the passenger miR-21-3p strand, in addition to the mature miR-21-5p strand, positively regulates KC proliferation through the upregulation of cyclin D1. Interestingly, Wang et al.…”