The Interaction of Senescent Cells and Macrophages in Fibrosis

The interaction between senescent cells and macrophages is of great importance to wound healing. Differences in the behavior of these two cell types appear critical to proficient regeneration in species like salamanders versus poor regeneration and scarring in mammals. Fibrosis is a malfunction of tissue maintenance and regeneration, in which excessive scarring takes place, disrupting tissue function and structure. This too is connected to the presence and behavior of senescent cells and macrophages. In old individuals, there is a background of raised inflammatory signaling and a growth in lingering senescent cells. One way to look at fibrosis is that this chronic inflammation and persistence of senescent cells interferes in the normal signaling between transient senescent cells and macrophages in regeneration and tissue maintenance, leading to pathological outcomes.

Senescent cells are attractive candidates as drivers of age-related organ dysfunction. They are consistently seen in diseased and older tissues when compared with healthy age-matched controls, actively secreting pro-inflammatory and pro-fibrotic molecules capable of driving further (paracrine) senescence and propagating on-going tissue damage. This is potentially because they secrete pro-inflammatory cytokines in the senescence-associated secretory phenotype (SASP) which modify the surrounding environment.

Macrophages contribute to clearance of senescent cells by phagocytosis. This activity declines with age in multiple organ systems, including the kidney, as macrophages polarize from M1 to M2 in response to exogenous growth factors, and can potentially become 'senescent-associated' and possibly senescent themselves. This is followed by a concurrent increase in fibrosis with age, which negatively affects organ function.

New therapy strategies have been developed, both pharmaceutical and lifestyle changes that aim at reducing the burden of senescent cells and the SASP they generate, and reducing inflammation, aimed at removing blockades for macrophage polarity transitions essential for response to injuries. In this review, we examine senescent cells and the overlap between the direct biological impact of senescence and the indirect impact senescence has via its effects on other cell types, particularly the macrophage. The canonical roles of macrophages in cell clearance and in other physiological functions are discussed with reference to their functions in diseases of the kidney and other organs. We also explore the translational potential of different approaches based around the macrophage in future interventions to target senescent cells, with the goal of preventing or reversing pathologies driven or contributed to in part by senescent cell load in vivo.

Link: https://doi.org/10.3389/fimmu.2021.700790

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