The Role of Aging Macrophages in Skin Inflammation

The immune system is complex and ages in complex ways, pressed by the lifetime burden of infection and rising levels of molecular damage that trigger many of the same innate immune responses as are produced by invading pathogens. The common innate immune cells known as macrophages play many roles in the body: defense against pathogens; destruction of errant cells; assisting in tissue maintenance and regeneration. Macrophages adopt different phenotypes (M1, M2, and others) depending on the task at hand.

The aging of the macrophage population, and also the analogous microglia of the central nervous system, is not as simple a matter as there being too many angry, inflammatory M1 macrophages and too few regenerative, anti-inflammatory M2 macrophages. There is, however, a sizable amount of evidence to suggest that this growing imbalance towards inflammatory macrophage behavior is a major cause of issues in older individuals. The perspective of this review paper on macrophage aging is a narrow one, focused on skin only, but much of the discussion is applicable to other tissues.

The skin is our largest organ. Its aging reflects both intrinsic (or chronological) and extrinsic (such as radiation and pollution exposure) aging processes at the molecular and phenotypic levels. Skin aging is a process accompanied by changes that alter the local microenvironment, such as weakening of the skin barrier and the accumulation of stressed and senescent cells, both of which foster inflammation through the invasion/release of Pathogen-Associated Molecular Patterns and Damage-Associated Molecular Patterns. The consequences of such an altered microenvironment include the promotion of the senescence-associated secretory phenotype (SASP), compromising tissue renewal and function, altered cellular interactions, and chronic low-grade inflammation. This sterile inflammatory state, termed inflammaging, develops in several organs with advanced age and is associated with persistent inflammation that ultimately exhausts the skin's defense system.

Macrophages (Mφ), a group of heterogeneous and plastic cells, play a central role in tissue homeostasis and repair, as well as host defense. In the skin, Mφ can be found in different layers, being classified as recruited Mφ originating from monocytes following a recruitment process started by tissue injury, or as tissue-resident macrophages (TRM), which are derived from both adult and embryonic progenitors. Mφ may acquire different phenotypes in response to various stimuli. In this sense, based on in vitro assays, Mφ have been divided into two groups based on their polarization phenotypes: M1 and M2. Classically activated Mφ are deemed as M1 and constitute catabolic, proinflammatory cells that are involved in antimicrobial host defense. M2, or alternatively activated Mφ, are anabolic cells with anti-inflammatory and tissue repair properties. However, mainly due to recent advances in single-cell RNA sequencing, it is now clear that such a dichotomy does not accurately represent Mφ in vivo but represents the extremes of a wide range of continuous phenotypes which have been reported.

The aging process has a great impact on Mφ, including alterations in Mφ metabolic and immune function, impacting the Mφ capability of clearance and immunosurveillance, constituting an important aspect of immunosenescence. In fact, old Mφ in a mice model were characterized with a senescent, proinflammatory profile, associated with increased oxidative stress, compromised antioxidant defenses, and impaired function. Mφ are considered as gatekeepers of tissue homeostasis and integrity, constituting primary inflammatory cytokine producers, as well as initiators and regulators of inflammation, and representing one of the main cellular players in adaptive immunity exacerbation and exhaustion during aging. In recognition of the age-related alterations on Mφ function and their importance during skin aging, in this review, we will dissect how aging hallmarks may alter the Mφ phenotype and function and connect these plastic cells with skin inflammaging.