Corneal Wound Healing Requires IKB kinase β Signaling in Keratocytes.

Liang Chen,Ying Xia,Qin Wang,Qinghang Meng,Maureen Mongan,Winston Kao,Dimitrios Karamichos

doi:10.1371/journal.pone.0151869

Abstract

IkB kinase β (IKKβ) is a key signaling kinase for inflammatory responses, but it also plays diverse cell type-specific roles that are not yet fully understood. Here we investigated the role of IKKβ in the cornea using IkkβΔCS mice in which the Ikkβ gene was specifically deleted in the corneal stromal keratocytes. The IkkβΔCS corneas had normal morphology, transparency and thickness; however, they did not heal well from mild alkali burn injury. In contrast to the IkkβF/F corneas that restored transparency in 2 weeks after injury, over 50% of the IkkβΔCS corneas failed to fully recover. They instead developed recurrent haze with increased stromal thickness, severe inflammation and apoptosis. This pathogenesis correlated with sustained myofibroblast transformation with increased α smooth muscle actin (α-SMA) expression, higher levels of senescence β-Gal activity and scar tissue formation at the late stage of wound healing. In addition, the IkkβΔCS corneas displayed elevated expression of hemo-oxygenase-1 (HO-1), a marker of oxidative stress, and activation of stress signaling pathways with increased JNK, c-Jun and SMAD2/3 phosphorylation. These data suggest that IKKβ in keratocytes is required to repress oxidative stress and attenuate fibrogenesis and senescence in corneal wound healing.

Highlights

IκB kinase β (IKKβ) is a key catalytic subunit of the IKK complex [1]
While the products of PCR amplification were detected in cells isolated from IkkβF/F corneas, they were absent in cells isolated from IkkβF/F/Kera-Cre corneas, though Gapdh used as control was amplified in both cells (Fig 1B)
We show that IkB kinase β (IKKβ) expression in keratocyte is dispensable for corneal development, but required for optimal wound healing

Summary

Introduction

IκB kinase β (IKKβ) is a key catalytic subunit of the IKK complex [1]. It plays a crucial role in the activation of NF-κB, which is a transcription factor that binds to κB elements in promoters and enhancers of target genes [2]. Stress stimuli can activate the IKKβ-NF-κB cascade, leading to either activation or repression of gene expression in a highly cell type-specific fashion. I.e. neutrophils and macrophages, this cascade leads to induction of genes coding for cytokines, chemokines, enzymes and molecules with microbicidal activity [3]. The immune cell IKKβ, plays a crucial role in protection against dangerous environmental stimuli. IKKβ is ubiquitously expressed in essentially all mammalian organisms, its role in non-immune cells is less well understood

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Conclusion