Inhibition of NUCKS Facilitates Corneal Recovery Following Alkali Burn

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.

Roles of NUCKS1 in Diseases: Susceptibility, Potential Biomarker, and Regulatory Mechanisms

“…In contrast, NUCKS1 has low expression in acute inflammatory diseases. This finding may be associated with the role of NUCKS1 as a transcription factor to regulate NF κ B activation and release NF κ B-mediated cytokines [ 53 ]. Furthermore, NUCKS1 is also downregulated in metabolic diseases [ 54 , 55 ].…”

“…However, in contrast to the cancers mentioned above, in adult T-cell leukemia-lymphoma (ATLL), NUCKS1 expression has been found to be lower than the average NUCKS1 expression across all specimens [ 51 ]. In addition, NUCKS1 is reduced in acute kidney injury (AKI) [ 52 ], and the inhibition of NUCKS1 plays a role in cytokine modulation and facilitates corneal recovery following alkali burn [ 53 ]. Intriguingly, NUCKS1 knockout (NKO) mice [ 54 ] and hypothalamus-specific deletion of NUCKS1 (HNKO) mice [ 55 ] exhibit decreased insulin signaling, increased body weight/fat mass, impaired glucose tolerance, and reduced insulin sensitivity.…”

“…In vivo studies results have suggested that the inhibition of NUCKS1 plays a role in cytokine modulation and facilitates corneal recovery [ 53 ]. Such inhibition decreases the angiogenic response and angiogenic vascular endothelial growth factor (VEGF) but increases antiangiogenic factors (such as pigment epithelium-derived factor (PEDF)) following in vivo alkali injury.…”

“…Following lipopolysaccharide- (LPS-) induced NF- κ B activation, NUCKS1 knockout corneal epithelial cells showed reduced expression of phosphorylated I κ B (P I κ B), interleukins (including IL6), IP10, and tumor necrosis factor α (TNF α ). Given the aforementioned data, NUCKS1 regulates NF- κ B, the expression of particular NF- κ B-mediated cytokines, and the phosphorylation of specific proteins critical to the NF- κ B signaling pathway in ocular epithelial cells [ 53 ]. Remarkably, in in vitro study, NUCKS1 has been shown to increase Tat-mediated transcriptional activity of the HIV-1 long terminal repeat (LTR) in an NF- κ B-independent manner [ 48 ] ( Figure 2 ).…”

Rap1 deficiency-provoked paracrine dysfunction impairs immunosuppressive potency of mesenchymal stem cells in allograft rejection of heart transplantation

“…Rap1 −/− -MSCs were grown at 37 °C, and 2 × 10 5 cells were seeded onto a 35-mm culture plate a day before transfection. Cells were transfected using Lipofectamine 2000 (Life Technologies, 11668019) with the respective constructs as described previously 36 . Cells were harvested 48 h after transfection, and the luciferase activity was determined according to the manufacturer’s instructions.…”