TGF-β and NF-κB signaling pathway crosstalk potentiates corneal epithelial senescence through an RNA stress response

Abstract

The corneal epithelium plays important roles in the maintenance of corneal transparency for good vision, and acts as a protective barrier against foreign insults. Structural and functional changes with aging in the corneal epithelium have been documented. Here we found that transforming growth factor-β (TGF-β) is highly expressed in the elderly donor corneal epithelium, as are senescence-associated genes, such as p16 and p21. In human corneal epithelial cell (HCEC) models, TGF-β induces cellular senescence, characterized by increased SA-β-gal positive cells and elevated expression of p16 and p21. Pharmacological inhibition of TGF-β signaling alleviates TGF-β-induced cellular senescence. In addition, we determined that senescence-associated inflammation was significantly aggravated in TGF-β-induced cellular senescence by detecting the expression of interleukin-6 (IL-6), IL-8, and tumor necrosis factor alpha (TNFα). Both genetic and pharmacological approaches revealed that blocking nuclear factor-κB (NF-κB) signaling not only inhibited the production of inflammatory factors, but also rescued the senescent phenotype induced by TGF-β in HCECs. Mechanistically, TGF-β induced an atypical RNA stress responses, leading to accelerated mRNA degradation of IκBα, an inhibitor of NF-κB. Together, our data indicate that TGF-β-driven NF-κB activation contributes to corneal epithelial senescence via RNA metabolism and the inflammation blockade can attenuate TGF-β-induced senescence.

Snail suppresses cellular senescence and promotes fibroblast‐led cancer cell invasion

“…Notwithstanding our findings in this study, TGF‐β induces cellular senescence in human corneal epithelial cells in cooperation with NF‐kB signals . Consistent with this, we already reported that TNF‐α signals cooperate with TGF‐β to induce the EMT in lung cancer A549 cells harboring active K‐Ras mutation, and NF‐kB inhibitor blocks the EMT .…”

Rapamycin Nano-Micelle Ophthalmic Solution Reduces Corneal Allograft Rejection by Potentiating Myeloid-Derived Suppressor Cells' Function

“…Corneal allografts and MDSCs were lysed in RIPA buffer (Beyotime, Beijing, China) with a protease inhibitor cocktail (Millipore), respectively. Western blot was performed as described previously ( 24 ). The membranes were probed with anti-GAPDH (KC-5G5, Kangchen) and anti-iNOS (ab15323, Abcam) primary antibodies and subsequently reacted with HRP-conjugated secondary antibodies (Pierce, 1:3,000), respectively.…”

Chronic exercise reduces hypothalamic transforming growth factor-β1 in middle-aged obese mice

“…The TGF-β protein has three different isoforms (1-3), located in the extracellular matrix and can regulate several biological cell functions such as proliferation, differentiation, migration, and survival, playing pivotal role in the morphogenesis and homeostasis [ 10 ]. This protein is expressed in different tissues including brain [ 9 ], tumor [ 11 ], corneal epithelium [ 12 ] and muscle [ 13 ]. There are some evidences that links the TGF-β1 levels with obesity and aging in rodents and humans [ 9 , 14 , 15 ].…”