Senescent cells: Living or dying is a matter of NK cells

Abstract

NK cells are lymphocytes of the innate immune system, which are able to deal promptly with stressed cells. Cellular senescence is a cell stress response leading to cell cycle arrest that plays a key role during tissue homeostasis and carcinogenesis. In this review, how senescent cells trigger an immune response and, in particular, the ability of NK cells to recognize and clear senescent cells are discussed. Special attention is given to the NK cell‐mediated clearance of senescent tumor cells. NK cells kill senescent cells through a mechanism involving perforin‐ and granzyme‐containing granule exocytosis, and produce IFN‐γ following senescent cell interaction, leading to hypothesize that NK cell‐mediated immune clearance of senescent cells not only relies on direct killing but also on cytokine production, that in turn can promote macrophage activation. These aspects, as well as the ability of the senescence‐associated secretory phenotype and senescent cell‐produced extracellular vesicles to modulate NK cell effector functions, are described.

Role of immune cells in the removal of deleterious senescent cells

“…DNA damage is known to induce the expression of several NK cell receptors, such as NKG2D and DNAX accessory molecule-1 (DNAM-1) ligand, on target cells [93]. This induction has been utilized to increase the immune clearance of multiple myeloma, where induction of senescence upon treatment with genotoxic chemotherapeutic drugs like Doxorubicin enhances NK cellmediated elimination of cancer cells due to increased expression of DNAM-1 [94][95][96]. In addition, recent studies show that senescent cells acquire mechanisms to evade clearance by NK cells.…”

Senescence as an Amyloid Cascade: The Amyloid Senescence Hypothesis

“…Senescent cells have been shown to be cleared by natural killer cells (NKs; Iannello et al, 2013;Eggert et al, 2016;Sagiv et al, 2016;Antonangeli et al, 2019;Muñoz et al, 2019;Pereira et al, 2019) and macrophages (Xue et al, 2007;Krizhanovsky et al, 2008;Kang et al, 2011;Muñoz-Espín et al, 2013). The way in which NKs kill senescent cells in the periphery is well-understood (Antonangeli et al, 2019). The activation of NKs depends on a complex interplay between their activator and inhibitory receptors.…”

The role of natural killer cells in Parkinson’s disease

“…NK cells as direct scavengers of α-syn species α-Syn deposition has been shown to promote the release of senescence-associated secretory (SASP) profiles from cells 100 , which converts senescent cells into continuous sources of proinflammatory mediators, reactive oxygen species and metalloproteinases 101,102 . NK cells can recognize and clear senescent cells through a mechanism involving perforin and granzyme-containing granule exocytosis and production of IFN-γ following senescent cell interaction 103 Therefore, NK cells may target senescent cells burdened with α-syn for lysis. Furthermore, human NK cells efficiently scavenge various forms of αsyn species 24 , making it plausible that NK cells can reduce the α-syn burden seen in PD patients.…”