Interferon regulatory factor 6 is required for proper wound healing in vivo.

Background: Van der Woude syndrome (VWS) is the most common form of syndromic orofacial cleft caused predominantly by mutations in Interferon Regulatory Factor 6 (IRF6). We previously reported that individuals with VWS have increased risk of wound healing complications following cleft repair compared with individuals with nonsyndromic orofacial clefts (nonsyndromic cleft lip and palate—NSCLP). In vitro, absence of IRF6 leads to impaired keratinocyte migration and embryonic wound healing. However, there is currently no data on tissue repair in adult animals and cells with reduced levels of IRF6 like in VWS. Results: Excisional wounds of Irf6+/− and wild‐type animals were analyzed 4 and 7 days post‐wounding. Although all wounds were reepithelialized after 7 days, the epidermal and wound volume of repaired wounds was larger in Irf6+/−. These data were supported by increased keratinocyte proliferation in the neoformed epidermis and a less mature granulation tissue with increased cytokine levels. This effect was not cell autonomous, as Irf6+/− neonatal keratinocytes in vitro did not exhibit defects in scratch wound closure or proliferation. Keratinocytes from individuals with VWS also migrated similarly to keratinocytes from NSCLP individuals. Conclusions: These data support a role for IRF6 in wound healing by regulating keratinocyte proliferation, granulation tissue maturation, and cytokine levels. Key Findings: Mice heterozygous for Irf6 have altered wound healing in vivo with increased epidermal volume and wound volume.The defect is likely due to increased proliferation in the newly formed epidermis and some persistence of myofibroblasts in the granulation tissue.Cytokine levels were upregulated in Irf6+/‐ compared to wild type mice.Neither proliferation nor migration of Irf6+/‐ keratinocytes in vitro was altered, suggesting a non‐cell autonomous effect.Cells from individuals with IRF6 mutations closed an in vitro scratch wound similarly to cells from individuals with NSCLP. [ABSTRACT FROM AUTHOR]