Hallmarks of Aging in Macrophages: Consequences to Skin Inflammaging

Abstract

The skin is our largest organ and the outermost protective barrier. Its aging reflects both intrinsic and extrinsic processes resulting from the constant insults it is exposed to. Aging in the skin is accompanied by specific epigenetic modifications, accumulation of senescent cells, reduced cellular proliferation/tissue renewal, altered extracellular matrix, and a proinflammatory environment favoring undesirable conditions, including disease onset. Macrophages (Mφ) are the most abundant immune cell type in the skin and comprise a group of heterogeneous and plastic cells that are key for skin homeostasis and host defense. However, they have also been implicated in orchestrating chronic inflammation during aging. Since Mφ are related to innate and adaptive immunity, it is possible that age-modified skin Mφ promote adaptive immunity exacerbation and exhaustion, favoring the emergence of proinflammatory pathologies, such as skin cancer. In this review, we will highlight recent findings pertaining to the effects of aging hallmarks over Mφ, supporting the recognition of such cell types as a driving force in skin inflammaging and age-related diseases. We will also present recent research targeting Mφ as potential therapeutic interventions in inflammatory skin disorders and cancer.

Keywords: age-associated diseases; aging; immunosenescence.

Figure 1

Hallmarks of aging in Mφ in the skin microenvironment. Skin inflammaging is fostered by different yet interconnected and synergistic aging hallmarks. Mφ are plastic cells that play a pivotal role in the immune system and have been associated with the persistent chronic inflammation levels found in aged skin. Skin inflammaging is characterized by a shift towards pro-inflammatory Mφ phenotypes, which promote further tissue inflammation in the skin microenvironment through the secretion of pro-inflammatory cytokines, activation of important inflammatory pathways, and increased oxidative stress. Chronic low-grade oxidative-inflammatory stress during the aging process is a key factor that stimulates a vicious cycle, contributing to age-associated disease onset. At the same time, the reduction of Mφ with an anti-inflammatory phenotype contributes to the decrease in antigen presentation and phagocytosis, contributing to tissue homeostasis disturbance.

Figure 2

Macrophage-centered approaches for chronic skin disease treatment. In recognition of the major role played by aged Mφ in oxi-inflammaging, which in turn has been recognized as a risk factor for the development of chronic inflammatory skin diseases, it is possible that Mφ-targeted therapies constitute a promising alternative for at least some inflammatory skin disorders.