Format

Send to

Choose Destination
J Invest Dermatol. 2019 Jul 31. pii: S0022-202X(19)32680-6. doi: 10.1016/j.jid.2019.07.694. [Epub ahead of print]

MicroRNA-34 family enhances wound inflammation by targeting LGR4.

Author information

1
Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China; Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institute, Stockholm, Sweden. Electronic address: jianminwu81@hotmail.com.
2
Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institute, Stockholm, Sweden.
3
Institute of Biomedical Science and School of Life Science, East China Normal University, Shanghai, China.
4
Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China.
5
Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institute, Stockholm, Sweden; Dermato-Venereology Clinic, Karolinska University Hospital, Stockholm, Sweden.
6
Department of Dermatology, Academic University Hospital, Uppsala, Sweden.
7
Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institute, Stockholm, Sweden; Dermato-Venereology Clinic, Karolinska University Hospital, Stockholm, Sweden. Electronic address: jakob.wikstrom@ki.se.
8
Institute of Biomedical Science and School of Life Science, East China Normal University, Shanghai, China. Electronic address: xyye@bio.ecnu.edu.cn.
9
Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institute, Stockholm, Sweden; Ming Wai Lau Centre for Reparative Medicine, Stockholm node, Karolinska Institute, Stockholm, Sweden. Electronic address: ning.xu@ki.se.

Abstract

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.

KEYWORDS:

Venous ulcer; chronic wound; inflammation; keratinocyte; microRNA-34; wound healing

PMID:
31376385
DOI:
10.1016/j.jid.2019.07.694

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center