MicroRNA-132 enhances transition from inflammation to proliferation during wound healing
Dongqing Li, … , Mona Ståhle, Ning Xu Landén
Dongqing Li, … , Mona Ståhle, Ning Xu Landén
Published June 29, 2015
Citation Information: J Clin Invest. 2015;125(8):3008-3026. https://doi.org/10.1172/JCI79052.
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Research Article Inflammation

MicroRNA-132 enhances transition from inflammation to proliferation during wound healing

Abstract

Wound healing is a complex process that is characterized by an initial inflammatory phase followed by a proliferative phase. This transition is a critical regulatory point; however, the factors that mediate this process are not fully understood. Here, we evaluated microRNAs (miRs) in skin wound healing and characterized the dynamic change of the miRNome in human skin wounds. miR-132 was highly upregulated during the inflammatory phase of wound repair, predominantly expressed in epidermal keratinocytes, and peaked in the subsequent proliferative phase. TGF-β1 and TGF-β2 induced miR-132 expression in keratinocytes, and transcriptome analysis of these cells revealed that miR-132 regulates a large number of immune response– and cell cycle–related genes. In keratinocytes, miR-132 decreased the production of chemokines and the capability to attract leukocytes by suppressing the NF-κB pathway. Conversely, miR-132 increased activity of the STAT3 and ERK pathways, thereby promoting keratinocyte growth. Silencing of the miR-132 target heparin-binding EGF-like growth factor (HB-EGF) phenocopied miR-132 overexpression in keratinocytes. Using mouse and human ex vivo wound models, we found that miR-132 blockade delayed healing, which was accompanied by severe inflammation and deficient keratinocyte proliferation. Together, our results indicate that miR-132 is a critical regulator of skin wound healing that facilitates the transition from the inflammatory to the proliferative phase.

Authors

Dongqing Li, Aoxue Wang, Xi Liu, Florian Meisgen, Jacob Grünler, Ileana R. Botusan, Sampath Narayanan, Erdem Erikci, Xi Li, Lennart Blomqvist, Lei Du, Andor Pivarcsi, Enikö Sonkoly, Kamal Chowdhury, Sergiu-Bogdan Catrina, Mona Ståhle, Ning Xu Landén

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Figure 7

Silencing of HB-EGF can mimic the effects of miR-132 overexpression in keratinocytes.

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Silencing of HB-EGF can mimic the effects of miR-132 overexpression in k...
qRT-PCR analysis of Ki-67 expression (n = 3) (A) and colony formation assays (n = 6) (B) were performed in keratinocytes transfected with HB-EGF–specific siRNA (siHB-EGF) or control siRNA (siControl). (C) Both phosphorylated and total EGFR, STAT3, and ERK were detected by Western blot analysis in EGF-treated keratinocytes with silenced HB-EGF expression. (D) Immunostaining of p-STAT3 and p-ERK in keratinocytes transfected with siControl or siHB-EGF for 48 hours, then treated with EGF for 15 minutes. Cells were counterstained with DAPI (blue, nucleus). (E) qRT-PCR analysis of chemokine expression in keratinocytes transfected with siControl or siHB-EGF (n = 3). (F) Both phosphorylated and total p65 were detected by Western blotting in TNF-α–treated keratinocytes with silenced HB-EGF expression. *P < 0.05, **P < 0.01, and ***P < 0.001 by Student’s t test.