Macrophages in age-related chronic inflammatory diseases

Abstract

Chronic inflammation is the common pathological basis for such age-associated diseases as cardiovascular disease, diabetes, cancer and Alzheimer's disease. A multitude of bodily changes occur with aging that contribute to the initiation and development of inflammation. In particular, the immune system of elderly individuals often exhibits diminished efficiency and fidelity, termed immunosenescence. But, although immune responses to new pathogens and vaccines are impaired, immunosenescence is also characterized by a basal systemic inflammatory state. This alteration in immune system function likely promotes chronic inflammation. Changes in the tissue microenvironment, such as the accumulation of cell debris, and systemic changes in metabolic and hormonal signals, also likely contribute to the development of chronic inflammation. Monocyte/macrophage lineage cells are crucial to these age-associated changes, which culminate in the development of chronic inflammatory diseases. In this review, we will summarize the diverse physiological and pathological roles of macrophages in the chronic inflammation underlying age-associated diseases.

Figure 1

Aberrant inflammatory response of a dendritic cell and macrophage with aging. Toll-like receptors (TLRs) are a family of pattern-recognition receptors that have a key role in the innate immune system. TLRs are activated by specific ligands derived from pathogens and damaged cells, as shown. The expression and function of some TLRs are downregulated with aging, potentially impairing immune responses. On the contrary, signaling mediated via TLR and IFNγ is activated, resulting in increased secretion of inflammatory cytokines. IFN, interferon; LPS, lipopolysaccharide; dsRNA, double-stranded RNA; ssRNA, single-stranded RNA.

Figure 2

Role of macrophages in the clearance of senescent cells. Senescent cells secrete proinflammatory mediators, senescence-associated secretory phenotype (SASP) factors. SASP factors recruit immune cells (macrophages, neutrophils and T cells), which then clear the senescent cells. In addition, CD4⁺ T cells are known to survey the antigens expressed in premalignant senescent hepatocytes and interact with monocytes/macrophages to clear those senescent cells. Note that the biological effects of SASP factors are not limited to the recruitment of immune cells. SASP factors may promote cell proliferation, differentiation and migration as well as extracellular matrix remodeling. Consequently, SASP factors likely contribute to tissue regeneration and healing. However, they may also promote inflammation in age-associated pathologies.