MicroRNA-34 family enhances wound inflammation by targeting LGR4.

Venous ulcers (VU) are the most common type of human chronic non-healing wounds and stalled in a constant and excessive inflammatory state. The molecular mechanisms underlying the chronic wound inflammation remains elusive. Moreover, little is known about the role of regulatory RNAs, such as microRNAs (miRNAs), in the pathogenesis of VU. We found that both miR-34a and miR-34c were upregulated in the wound-edge epidermal keratinocytes of VU compared with normal wounds or the skin. In keratinocytes, miR-34a and miR-34c promoted inflammatory chemokine and cytokine production. In wounds of wild-type mice, miR-34a mimic treatment enhanced inflammation and delayed healing. To further explore how miR-34 function, LGR4 was identified as a direct target mediating the pro-inflammatory function of miR-34a and miR-34c. Interestingly, impaired wound closure with enhanced inflammation was also observed in Lgr4 KO mice. Mechanistically, miR-34-LGR4 axis regulated GSK-3β -induced p65 Ser468 phosphorylation, changing the activity of NF-κB signaling pathway. Collectively, the miR-34-LGR4 axis was shown to regulate keratinocyte inflammatory response, which deregulation may play a pathological role in VU.