TGF-β as A Master Regulator of Aging-Associated Tissue Fibrosis

Figures

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  Figure 1.. Mechanisms of fibrosis. Aging, injury, infection, and inflammation can promote epithelial cells to myofibroblast transition, regulate ECM formation and remodelling, and ultimately lead to tissue fibrosis or efficient repair. Activated epithelial cells secrete many inflammatory mediators, such as TGF-β1 and interleukin-1β, which recruit immune cells such as mast cells, B cells, T cells, and macrophages. These invasive immune cells release TGF-β, interleukin-1β, interleukin-6, interleukin-13, and other mediators, enhancing profibrotic reactions.

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  Figure 2.. The role of cellular senescence in fibrosis. Cellular senescence is caused by telomere damage, epigenetic dysregulation, DNA damage, oxidative stress, mitochondrial dysfunction, proteostatic dysfunction, and mitochondrial dysfunction. Acute cellular senescence produced early in life provides a benefit during tissue fibrosis, but the aberrant and chronic accumulation of senescent cells late in life drives various features of aging, including age-related fibrosis.

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  Figure 3.. The TGF-β signalling pathway in aging and fibrosis. TGF-β is an inactive complex formed by the combination of TGF-β with a latency-associated peptide. Latent activation of TGF-β in fibrotic illnesses may involve ROS, aging, and integrins. NOX is one of the key enzymes linking ROS and TGF-β activity. Different NOX subtypes contribute to the production of intracellular ROS. ROS overproduction can lead to DNA damage. ROS interacts with classical and nonclassical TGF-β signalling pathways to regulate inflammation and the expression of the PAI-1, P21, fibronectin, TGF-β, and NOX4 genes. ATM, ataxia telangiectasia mutated protein; JNK, c-Jun terminal kinase; NF-κB, nuclear factor-kappa B; NOX, NADPH oxidase; PAI-1, plasminogen activator inhibitor-1; ROS, reactive oxygen species; TAK1, TGF-β-activated kinase 1; TRAF, TGF-β receptor-associated factor.