Phagocyte dysfunction, tissue aging and degeneration

Abstract

Immunologically-silent phagocytosis of apoptotic cells is critical to maintaining tissue homeostasis and innate immune balance. Aged phagocytes reduce their functional activity, leading to accumulation of unphagocytosed debris, chronic sterile inflammation and exacerbation of tissue aging and damage. Macrophage dysfunction plays an important role in immunosenescence. Microglial dysfunction has been linked to age-dependent neurodegenerations. Retinal pigment epithelial (RPE) cell dysfunction has been implicated in the pathogenesis of age-related macular degeneration (AMD). Despite several reports on the characterization of aged phagocytes, the role of phagocyte dysfunction in tissue aging and degeneration is yet to be fully appreciated. Lack of knowledge of molecular mechanisms by which aging reduces phagocyte function has hindered our capability to exploit the therapeutic potentials of phagocytosis for prevention or delay of tissue degeneration. This review summarizes our current knowledge of phagocyte dysfunction in aged tissues and discusses possible links to age-related diseases. We highlight the challenges to decipher the molecular mechanisms, present new research approaches and envisage future strategies to prevent phagocyte dysfunction, tissue aging and degeneration.

Keywords: Aging; Macrophage; Microglia; Phagocyte dysfunction; Phagocytosis; Retinal pigment epithelium.

Fig. 1

Phagocytosis through different phagocytic receptors has distinct outcomes of innate immune response. Phagocytosis of infectious pathogens by macrophage and microglia through Toll-like receptors (TLRs), Fc receptors (FcRs), complement receptors (CRs) and scavenger receptors (SRs) induces pro-inflammatory response. In contrast, phagocytosis of autologous apoptotic cells or cellular debris via phosphatidylserine (PS) receptors (e.g., BAI1, stabilin-2 and Tim-4), MerTK, αvβ3 or αvβ5 integrins, TREM2, FcRs, CRs and SRs elicits anti-inflammatory response.

Fig. 2

Mechanisms of tissue degeneration accelerated by phagocyte dysfunction. Phagocyte aging and dysfunction can disrupt tissue homeostasis and innate immune balance through different mechanisms, thereby exacerbating tissue damage and degeneration.