SENESCENCE CLEARANCE

Mechanisms of immune surveillance of senescent cells

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 Obiettivo del progetto (Objective)

'Cellular senescence, a stable form of cell cycle arrest, is a mechanism limiting the proliferative potential of cells. Recent studies demonstrate that cellular senescence imposes a potent barrier to tumorigenesis and contributes to the cytotoxicity of certain anticancer agents. In addition to sites of persistent damage and precancerous lesions, senescent cells have also been observed in tissues of aged individuals and can contribute to decline of tissue function with age. Therefore, mechanisms responsible for control over presence of senescent cells play central role in cancer prevention and aging. In my post-doctoral training I was first to demonstrate that cellular senescence protects against liver fibrosis, and that senescent cells can be cleared by the innate immune system to insure return to the pre-damage state. Components of the innate immune system, macrophages and NK cells were also demonstrated to clear senescent cell from tumors. However, molecular mechanisms of the recognition and the killing of senescent cells remain to be understood. Therefore, I propose to study contribution of NK cells and macrophages to recognition and elimination of senescent cells. Molecular mechanisms responsible for these interactions will be studied using engineered cell lines were senescence can be induced. Elaborate short hairpin RNA techniques will allow discovery of genes in senescent cells that are responsible for signaling to immune cells from one side, and from the other side identification of molecules in immune cells that can contribute to senescent cell elimination. Uncovering the mechanisms of interaction of senescent cells with the immune system will reveal the role of these interactions in diseases and aging and might ultimately lead to development of novel treatments.'

Introduzione (Teaser)

When cells grow old or receive stress signals, they undergo a process known as cellular senescence. Understanding the fate of these cells in an organism could help prevent cancer formation and ageing.

Descrizione progetto (Article)

Cellular senescence basically entails the cessation of growth and is associated with a reduction in expression of growth-promoting genes and upregulation of cell cycle inhibitors. Additionally, changes are observed in the expression of secreted molecules involved in extracellular matrix production and immune surveillance.

At the molecular level, the senescence programme is governed by the interplay between the retinoblastoma Rb and p53 tumour suppressor networks, and DNA damage response. In culture, senescent cells can continue to grow indefinitely, but their fate in tissues is not well understood and seems to be cell-specific. For example, senescent melanocytes can remain in the skin throughout life while senescent liver cells get cleared by the immune system.

To further explore this phenomenon, scientists on the EU-funded 'Mechanisms of immune surveillance of senescent cells' (SENESCENCE CLEARANCE) project set out to investigate the role of the immune system in clearance of senescent cells. Researchers had previously shown that the presence of senescent cells within a tissue directly affects the local microenvironment. In the liver, the clearance of senescent cells takes place by natural killer (NK) cells, thereby limiting the emergence of fibrosis.

During the SENESCENCE CLEARANCE study, scientists were able to show that senescent cells express higher levels of ligands that are recognised by NK receptors. Clearance seems to be driven by granule exocytosis, and mice with defects in this process accumulate senescent cells and display more severe liver fibrosis. Research into the mechanism identified the decoy death receptor Dcr2 as an important determinant of resistance of senescent cells to apoptosis and NK-mediated cell death.

The role of the immune system in the clearance of senescent cells is not limited to NK cells. Researchers found that senescent cells also attract macrophages that in turn recognise and engulf senescent cells.

Taken together, findings from the SENESCENCE CLEARANCE project underscore the significance of immune surveillance in the clearance of senescent cells. Given the association of senescence with ageing and tumour onset, these results could form the basis for future anticancer therapies.