Abstract
NF-κB is constitutively activated in psoriatic epidermis. However, how activated NF-κB promotes keratinocyte hyperproliferation in psoriasis is largely unknown. Here we report that the NF-κB activation triggered by inflammatory cytokines induces the transcription of microRNA (miRNA) miR-31, one of the most dynamic miRNAs identified in the skin of psoriatic patients and mouse models. The genetic deficiency of miR-31 in keratinocytes inhibits their hyperproliferation, decreases acanthosis and reduces the disease severity in psoriasis mouse models. Furthermore, protein phosphatase 6 (ppp6c), a negative regulator that restricts the G1 to S phase progression, is diminished in human psoriatic epidermis and is directly targeted by miR-31. The inhibition of ppp6c is functionally important for miR-31-mediated biological effects. Moreover, NF-κB activation inhibits ppp6c expression directly through the induction of miR-31, and enhances keratinocyte proliferation. Thus, our data identify NF-κB-induced miR-31 and its target, ppp6c, as critical factors for the hyperproliferation of epidermis in psoriasis.
Highlights
NF-kB is constitutively activated in psoriatic epidermis
To identify miRNAs that are preferentially expressed in inflamed keratinocytes, we carried out comparative miRNA screening of normal ear skin from control mice and of lesional ear skin from CD18 hypomorphic (CD18hypo) mice, which spontaneously develop a T-cell-mediated psoriasiform skin disease[22]
By quantitative real-time PCR, we determined that miR-31 was significantly increased in the lesional skin from IMQ-treated mice compared with the healthy skin (1±0.2276 versus 3.877±0.4426, n 1⁄4 13, Po0.0001, two-tailed Student’s t-test) (Fig. 1c), and the upregulated miR-31 was mainly confined to epidermis (Fig. 1d)
Summary
NF-kB is constitutively activated in psoriatic epidermis. how activated NF-kB promotes keratinocyte hyperproliferation in psoriasis is largely unknown. The tumour necrosis factor-a (TNF-a)-targeting agent etanercept markedly inhibits p65 phosphorylation in the epidermal compartment, which is accompanied with an attenuation of epidermal thickness, restoration of keratinocyte differentiation molecular indicators and favourable clinical outcomes of psoriasis patients[7]. These studies strongly suggest a critical role of epidermal NF-kB activation in the pathophysiology of the disease. Despite the importance of the activated NF-kB pathway in epidermal hyperplasia of psoriasis, the critical intrinsic factor(s) that triggers basal keratinocyte hyperproliferation in the downstream of NF-kB signalling is not well-defined
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