IκB Kinase β Regulates Epithelium Migration during Corneal Wound Healing

Abstract

The IKKβ is known to regulate transcription factor NF-κB activation leading to inflammatory responses. Recent gene knockout studies have shown that IKKβ can orchestrate local inflammatory responses and regulate homeostasis of epithelial tissues. To investigate whether IKKβ has an intrinsic role in epithelial cells, we established an in vivo system in the immune privileged corneal epithelium. We generated triple transgenic Krt12rtTA/rtTAt/tet-O-Cre/IkkβF/F (IkkβΔCE/ΔCE) mice by crossing the Krt12-rtTA knock-in mice, which express the reverse tetracycline transcription activator in corneal epithelial cells, with the tet-O-Cre and IkkβF/F mice. Doxcycline-induced IKKβ ablation occurred in corneal epithelial cells of triple transgenic IkkβΔCE/ΔCE mice, but loss of IKKβ did not cause ocular abnormalities in fetal development and postnatal maintenance. Instead, loss of IKKβ significantly delayed healing of corneal epithelial debridement without affecting cell proliferation, apoptosis or macrophage infiltration. In vitro studies with human corneal epithelial cells (HCEpi) also showed that IKKβ was required for cytokine-induced cell migration and wound closure but was dispensable for cell proliferation. In both in vivo and in vitro settings, IKKβ was required for optimal activation of NF-κB and p38 signaling in corneal epithelial cells, and p38 activation is likely mediated through formation of an IKKβ-p38 protein complex. Thus, our studies in corneal epithelium reveal a previously un-recognized role for IKKβ in the control of epithelial cell motility and wound healing.

Temporal Smad7 Transgene Induction in Mouse Epidermis Accelerates Skin Wound Healing

“…Previously, activation of Erk and NF-B pathways have been shown to positively regulate keratinocyte proliferation and migration. 22,23,[32][33][34] In our current study, Erk expression was increased, whereas that of NF-B was decreased in Smad7 tg keratinocytes. We show that increased Erk activation in Smad7 tg keratinocytes contributed to accelerated keratinocyte migration.…”

The SULFs, Extracellular Sulfatases for Heparan Sulfate, Promote the Migration of Corneal Epithelial Cells during Wound Repair

“…It should be noted that a number of other growth factors implicated in corneal wound closure and/or corneal cell migration (IL-1ß, TNF-α, TGF-α, TGF-ß1, HGF, and KGF) [7], [68], [69] are able to bind heparin/HSPGs (reviewed in [11]) and are thus potentially subject to direct mobilization by SULFs. Because of their proximal position in signaling, the SULFs can influence the activity of more than one HSPG-binding growth factor and thus have pleotropic downstream effects, as has been demonstrated in glioma cells [25].…”

Accelerated In Vitro Degradation of Optically Clear Low–β Sheet Silk Films by Enzyme-Mediated Pretreatment

“…In each lamella, type I and type V collagen fiber bundles run parallel to each other with regular interfibrillar spacing. Collagen fibrils in the stroma show preferred alignment in horizontal and vertical directions 3, 7–9 arranged in a pseudo crystalline lattice orientation 2, 10 . The specific collagen orientation contributes to the mechanical strength and the optical clarity of the cornea 3, 11 .…”