Age-dependent dysregulation of innate immunity

Abstract

Key Points

The diverse cell lineages that mediate innate immunity show heterogeneous ageing phenotypes that reflect their different developmental, tissue and activation contexts.

In general, ageing of the innate immune system is characterized by dysregulated inflammatory responses that may contribute to a heightened pro-inflammatory milieu, particularly in humans. In the context of such persistent inflammation, failure in innate immune activation may occur in response to pathogens or vaccines.

Neutrophils in aged humans show decreased functions, as assessed by intracellular killing, chemotaxis and phagocytosis, and these defects may be due to reduced signalling induced by granulocyte/macrophage colony-stimulating factor, triggering receptor expressed on myeloid cells 1, and alterations in membrane lipid raft domains. Intracellular killing and phagocytosis by neutrophils from aged mice are generally preserved, although deficits in neutrophil extracellular trap formation, chemokine production and recruitment are seen.

Toll-like receptor (TLR) function in monocytes, macrophages and dendritic cell (DC) populations is generally decreased with age in humans and in mice. Both transcriptional and post-transcriptional mechanisms contribute to alterations in TLR expression. Furthermore, examples of increased TLR function in monocyte-derived DCs and West Nile virus-infected macrophages, together with evidence for increased basal cytokine production by DCs, reflect innate immune dysregulation.

Systemic factors, such as age-associated alterations in sex steroids, chronic viral infections (for example, with cytomegalovirus), lipotoxicity arising from metabolic syndrome and DNA damage, could contribute ligands for pattern recognition receptors, such as TLRs and NLRP3 (NOD-, LRR- and pyrin domain-containing 3), thereby potentiating an age-associated inflammatory environment.

The consequences of innate immune ageing are reflected in diverse tissues and organs, and this has potential implications for age-associated chronic inflammatory conditions, including Alzheimer's disease, atherosclerosis and metabolic syndrome.

Ageing is associated with impaired immune responses to pathogens and vaccines. As described in this Review, ageing results in disrupted regulation of immune cell functions and innate immune receptor signalling, and in the establishment of a persistent pro-inflammatory milieu. The authors explain how this age-associated dysregulation might contribute to chronic inflammatory diseases in the elderly.