Abstract
Corneal wound healing involves a complex cascade of cytokine-controlled cellular events, including inflammatory and angiogenesis responses that are regulated by transcriptional chromatin remodeling. Nuclear Ubiquitous Casein and cyclin-dependent Kinase Substrate (NUCKS) is a key chromatin modifier and transcriptional regulator of metabolic signaling. In this study, we investigated the role of NUCKS in corneal wound healing by comparing its effects on corneal alkali burn in NUCKS knockout (NKO) and NUCKS wild-type (NWT) mice. Our data showed that following alkali-injury, inhibition of NUCKS (NKO) accelerated ocular resurfacing and suppressed neovascularization; the cytokine profile of alkali burned corneas in NKO mice showed suppressed expression of inflammation cytokines (IL1A & IL1B); upregulated expression of antiangiogenic factor (Pigment Epithelium-derived Factor; PEDF); and downregulated expression of angiogenic factor (Vascular Endothelial Growth Factor, VEGF); in vitro, following LPS-induced NFκB activation, NKO corneal cells showed reduced expression of IL6, IP10 and TNFα. In vitro, corneal epithelial cells showed reduced NF-κb activation on silencing of NUCKS and corresponding NFκB-mediated cytokine expression was reduced. Here, we illustrate that inhibition of NUCKS played a role in cytokine modulation and facilitated corneal recovery. This reveals a potential new effective strategy for ocular burn treatment.
Highlights
DNA binding proteins have been described in the feedback loop of the cytokine induced cascade[2,3,4,5,6]
Corneal recovery was notably faster in the NUCKS knockout (NKO) group compared with the NUCKS wild-type (NWT) group
The NKO group showed reduced expression of various pro-inflammatory cytokines (IL617, IP1018 and TNFα19) compared with the NWT group (Fig. 8Ci and ii). (Full-length western blot images are presented in Supplementary Figure S2). Cellular events, such as cell movement, apoptosis and cell proliferation, followed by scar formation are critical to the corneal recovery process[1,2]
Summary
DNA binding proteins have been described in the feedback loop of the cytokine induced cascade[2,3,4,5,6]. Recent research has further suggested a potential role of NUCKS in stress responses leading to selective regulation of gene transcription[12]. These reports show that NUCKS shares many of the important functional properties which are important in modulation of corneal wound healing as well as an ability to precisely regulate the inflammatory response and cytokine release[3]. Our results showed that compared with NWT, NKO mice exhibited faster corneal resurfacing and suppressed angiogenic responses that was associated with fine modulation of cytokines: inflammatory www.nature.com/scientificreports/. Corneal defeat recovery in NKO mice was significantly faster than that for NWT mice at the end point, post injury day 14. Silencing of NUCKS and stimulation with LPS resulted in reduced NFκB signaling activation and reduced expression of cytokines downstream of the NFκB pathway
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