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⇱ Age-dependent dysregulation of innate immunity | Nature Reviews Immunology

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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.

Abstract

As we age, the innate immune system becomes dysregulated and is characterized by persistent inflammatory responses that involve multiple immune and non-immune cell types and that vary depending on the cell activation state and tissue context. This ageing-associated basal inflammation, particularly in humans, is thought to be induced by several factors, including the reactivation of latent viral infections and the release of endogenous damage-associated ligands of pattern recognition receptors (PRRs). Innate immune cell functions that are required to respond to pathogens or vaccines, such as cell migration and PRR signalling, are also impaired in aged individuals. This immune dysregulation may affect conditions associated with chronic inflammation, such as atherosclerosis and Alzheimer's disease.

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Figure 1: Organ-specific changes of the innate immune system associated with ageing and disease.
The alternative text for this image may have been generated using AI.
Figure 2: Effects of ageing on innate immune PRR signalling.
The alternative text for this image may have been generated using AI.

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Acknowledgements

We apologize to colleagues whose work we were unable to discuss due to space limitations. Work in this Review was supported by the US National Institutes of Health grants N01 272201100019C-3-0-1 and U19 AI089992 (to A.C.S. and R.R.M.), AG042489 (to A.C.S.), and AG028082 and AG033049 (to D.R.G.). D.R.G. is also supported by an Established Investigator Award from the American Heart Association (grant 094006N).

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Authors and Affiliations

  1. Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, 06520, Connecticut, USA

    Albert C. Shaw

  2. Department of Internal Medicine, Section of Cardiology, Yale School of Medicine, New Haven, 06520, Connecticut, USA

    Daniel R. Goldstein

  3. Department of Immunobiology, Yale School of Medicine, New Haven, 06520, Connecticut, USA

    Daniel R. Goldstein

  4. Department of Internal Medicine, Section of Rheumatology, Yale School of Medicine, New Haven, 06520, Connecticut, USA

    Ruth R. Montgomery

Authors
  1. Albert C. Shaw
  2. Daniel R. Goldstein
  3. Ruth R. Montgomery

Corresponding author

Correspondence to Albert C. Shaw.

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The authors declare no competing financial interests.

Glossary

Plasmacytoid dendritic cells

(pDCs). Immature DCs with morphology that resembles that of a plasma cell. Mouse pDCs express markers such as B220, which is usually associated with the B cell lineage. In humans, pDCs express CD123 and blood DC antigen 2 (BDCA2; also known as CLEC4C and CD303), and are CD11cβˆ’. These DCs are the main producers of type I interferons in response to viral infection.

Conventional DCs

Specialized phagocytic antigen-presenting cells that have the classic stellate dendritic cell (DC) morphology. Mouse conventional DCs generally express CD11c, but are highly heterogeneous and are divided into subsets: CD8Ξ±+ and CD4+ subsets in secondary lymphoid organs, and CD8Ξ±+CD103+ and CD4+CD11b+ subsets in the periphery. Human conventional DCs are generally termed myeloid DCs and are lineage-negative MHC class II+CD11c+ DCs. Human equivalents to the mouse CD8Ξ±+ and CD4+ subsets can be distinguished by expression of blood DC antigen 3 (BDCA3; also known as CD141) and BDCA1 (also known as CD1c), respectively.

Monocyte-derived DCs

(MDDCs). MDDCs can be generated in vitro from peripheral blood mononuclear cells in the presence of interleukin-4 and granulocyte/macrophage colony-stimulating factor. MDDCs resemble myeloid dendritic cells (DCs) and may model the differentiation of DCs from monocytes that enter sites of inflammation.

NOD-like receptors

(NLRs). A family of more than 20 nucleotide-binding oligomerization domain (NOD)-like cytoplasmic pattern recognition receptors that sense pathogens, toxins, endogenous danger signals (such as uric acid) and exogenous crystalline substances (such as alum, silica and asbestos) and induce inflammatory responses.

RIG-I-like receptors

(RLRs). A family of cytoplasmic pattern recognition receptors that are related to the RNA helicase retinoic acid-inducible gene I (RIG-I). They recognize single- and double-stranded viral RNA and mediate antiviral responses, such as type I interferon production.

Inflammasome

A multiprotein complex that consists of a NOD-like receptor, an adaptor protein and pro-caspase 1. On assembly, the complex facilitates the caspase 1-mediated cleavage and production of mature cytokines, such as interleukin-1Ξ² and interleukin-18.

Macroautophagy

An evolutionarily conserved process in which acidic double-membrane vacuoles sequester intracellular contents (such as damaged organelles and macromolecules) and, through fusion to secondary lysosomes, target them for degradation.

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Shaw, A., Goldstein, D. & Montgomery, R. Age-dependent dysregulation of innate immunity. Nat Rev Immunol 13, 875–887 (2013). https://doi.org/10.1038/nri3547

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