An Enhanced Natural Killer Cell Therapy Clears Senescent Cells in Mice
A growing burden of senescent cells in tissues throughout the body is an important contributing cause of degenerative aging. These cells secrete pro-growth, pro-inflammatory signals that, when maintained for the long term, are highly disruptive of cell and tissue function. Cellular senescence is an important contributing cause in many age-related conditions. Senescent cells are created constantly throughout life, and the immune system is responsible for removing those that fail to destroy themselves. Unfortunately, it becomes worse at this task with age.
Natural killer cells are one of the immune cell populations involved in senescent cell clearance, and researchers are interested in ways to enhance this ability. One possibility is to increase the number of natural killer cells present in the body. In today's open access paper, rsearchers here show that providing additional natural killer cells in the form of a cell therapy can reduce the burden of senescent cells in mice. They additionally propose ways to enhance the ability of transplanted cells to clear lingering senescent cells.
Senescent cells (SNCs) can be recognized and removed by the immune system. Previous studies have shown that SNCs activate natural killer (NK) cells by up regulating the major histocompability class I chain-related protein A and B activating ligand. However, with increasing age, the efficiency of the immune system decreases, which can lead to the immune escape of SNCs. Methods to overcome immune escape caused by decreased immune function have been explored in cancer therapy. Recent progress has been made in adoptively transferring NK cells to eliminate tumours, which has shown some efficacy; thus, it was reasonable to assume that the adoptive infusion of NK cells might produce cytotoxicity in SNCs.
The nervous and immune systems are the two most important adaptive systems of the body. Several studies have shown that dopamine (DA) as an immune regulator is a key to the neuroimmune communication. DA performs its biological functions by interaction with and activation of dopamine receptors (DR), which are divided into 2 subgroups, D1-like (D1 and D5), and D2-like (D2, D3, and D4). In terms of their different functions, the engagement of D1-like DR stimulates cAMP production, while the engagement of D2-like DR inhibits cAMP production. Previous studies have shown that D1-like DR stimulation enhances the cytotoxicity of NK cells both in vitro and in vivo. However, DA levels drop as human age increase. Thus, we hypothesized that dopaminergic drugs could enhance cytotoxicity of the adoptive infusion of NK cells.
Here, we propose the use of the nonapeptide Acein, which interacted with angiotensin converting enzyme (ACE I) to induce DA secretion, in combination with systemic NK cell therapy to eliminate SNCs. In vitro results showed that NK cells removed SNCs, independently of senescence inducers and cell types. In an aging mouse model, NK cell therapy in combination with Acein significantly reduced the number of senescence-associated β-galactosidase (SA-β-gal)-positive cells in multiple tissues, decreased the expression of senescence-associated genes in major organs, and alleviated senescence-associated secretory phenotypes (SASPs). The results of this study provide insights into possible restoration of the immune surveillance of chronic SNCs using NK cell therapy in combination with Acein.