Inflammatory networks during cellular senescence: causes and consequences

Abstract

Chronic inflammation is associated with aging and plays a causative role in several age-related diseases such as cancer, atherosclerosis and osteoarthritis. The source of this chronic inflammation is often attributed to the progressive activation of immune cells over time. However, recent studies have shown that the process of cellular senescence, a tumor suppressive stress response that is also associated with aging, entails a striking increase in the secretion of proinflammatory proteins and might be an important additional contributor to chronic inflammation. Here, we list the secreted factors that make up the proinflammatory phenotype of senescent cells and describe the impact of these factors on tissue homeostasis. We also summarize the cellular pathways/processes that are known to regulate this phenotype--namely, the DNA damage response, microRNAs, key transcription factors and kinases and chromatin remodeling.

Figure 1. Chronic inflammation is associated with most age-related diseases

There is an extensive range of conditions and diseases that are associated with chronic inflammation or that have an inflammatory component. Chronic inflammation lies at the root of heart disease, cancer, osteoporosis, Alzheimer’s disease, diabetes and many other age-related diseases.

Figure 2. Effects of the SASP on tissue homeostasis

The response of cells to the SASP depends on cell type and cell context. The SASP affects the original senescent cell by stimulating clearance by NK cells and reinforcing the senescence growth arrest. The SASP affects surrounding non-immune cells as well; it increases the proliferation of nearby epithelial and stromal cells, promotes invasion of any nearby preneoplastic or neoplastic cells via an epithelial to mesenchymal transition, stimulates angiogenesis by stimulating endothelial cell migration and invasion, and disrupts normal tissue structures and function.

Figure 3. Pathways that regulate the SASP

A senescence-inducing stimulus causes genotoxic stress (e.g. DNA damage or chromatin unwinding), which activates the DDR and p38MAPK pathways. These pathways cooperate to activate NF-κB. C/EBPβ is activated through an unknown mechanism. NF-κB and C/EBPβ activate the transcription of SASP genes. IL-1α, which is regulated by NF-κB, further increases NF-κB activity via a positive feedback loop; this loop is dampened by mir146a/b, which are also induced by NF-κB. This complex regulatory network increases the expression of pro-inflammatory factors, which are then secreted. Green arrows indicate activation of the SASP; red lines indicate inhibition of the SASP; blue boxes are upstream signaling components; yellow boxes are transcription factors.