Role of immune cells in the removal of deleterious senescent cells

Abstract

Cellular senescence is an essentially irreversible arrest of cell proliferation coupled to a complex senescenceassociated secretory phenotype (SASP). The senescence arrest prevents the development of cancer, and the SASP can promote tissue repair. Recent data suggest that the prolonged presence of senescent cells, and especially the SASP, could be deleterious, and their beneficial effects early in life can become maladaptive such that they drive aging phenotypes and pathologies late in life. It is therefore important to develop strategies to eliminate senescent cells. There are currently under development or approved several immune cell-based therapies for cancer, which could be redesigned to target senescent cells. This review focuses on this possible use of immune cells and discusses how current cell-based therapies could be used for senescent cell removal.

On the evolution of cellular senescence

“…After wound healing/ tissue remodeling is completed, senescent cells are removed. This is normally performed by the immune system and it seems that various cell types from macrophages and natural killer cells to cytotoxic T cells are involved in the process (Burton & Stolzing, 2018;Kale et al, 2020;Yun et al, 2015). Indeed, immunocompromised mice that have defective cytotoxic T cells develop chronic inflammation, accumulate senescent cells much faster and die 20% earlier (Ovadya et al, 2018).…”

“…Furthermore, senescent cells are quite heterogeneous regarding their transcriptional profile and SASP composition, depending on the original cell type and type of induction of cellular senescence (Coppe et al, 2010;Hernandez-Segura et al, 2017, which complicates a common recognition mechanism even more. Various mechanisms exist by which cells of the immune system recognize senescent cells (Burton & Stolzing, 2018;Kale et al, 2020), and recent observations indicate that senescent cells can actively influence their own clearance. Pereira et al (2019) showed that senescent cells express the non-canonical MHC molecule HLA-E, which interacts with inhibitory receptors on natural killer and CD8 cells, leading to a diminished immune clearance.…”

Periodontal Disease and Senescent Cells: New Players for an Old Oral Health Problem?

“…Due to their resistance to apoptosis [ 66 ], senescent cells persist in tissues and they can promote a negative impact on their environment through various mechanisms. First, as mentioned above, senescent cells become proinflammatory foci scattered throughout tissues promoting immune cell infiltration that results in collateral tissue damage over time [ 67 , 68 ]. Besides the exacerbation of local inflammation, senescent cells also constitute an important source of factors that contribute to age-related systemic chronic inflammation [ 69 ].…”

“…Besides pathogenic bacteria elimination, the host immune system detects and removes damaged cells, including senescent cells. This process is called senescent cell immune surveillance, in which the release of senescence-associated proinflammatory signals play essential roles in attracting neutrophils, macrophages, lymphocytes and natural killer cells [ 67 , 83 , 85 ]. However, reduced immunosurveillance of senescent cells accelerates their accumulation, resulting in gradual tissue deterioration and contributing to the development of different chronic pathologies [ 65 ].…”

Senescent cells and macrophages: key players for regeneration?

“…Macrophages are recruited to the site of injury by chemokine gradients and various adhesion molecules, where they carry out their role as scavenger cells that phagocytose cellular debris and invading cells, alongside other apoptotic cells, in response to tissue injury. Importantly, macrophages are key for the clearance of senescent cells following injury [ 48 , 49 ], as well as an important source of chemokines, matrix metalloproteinases (MMPs) and other inflammatory mediators which drive the initial cellular response [ 50 ]. Current models suggest that senescence initiates tissue modelling/remodelling by recruiting immune cells through the SASP, where macrophages clear senescent cells, allowing for repopulation by progenitor cells and regeneration of the damaged tissue [ 25 , 26 , 51 ].…”