Elsevier

Immunology Letters

Volume 230, February 2021, Pages 1-10
Immunology Letters

The impact of ageing on monocytes and macrophages

https://doi.org/10.1016/j.imlet.2020.12.003Get rights and content

Highlights

  • Chronic low-grade inflammation – inflammageing- is observed with age.

  • Macrophages and monocytes are central to the development of inflammageing.

  • In this review we detail how ageing alters the phenotype and function of monocytes and macrophages.

Abstract

Ageing is a global burden. Increasing age is associated with increased incidence of infections and cancer and decreased vaccine efficacy. This increased morbidity observed with age, is believed to be due in part to a decline in adaptive immunity, termed immunosenescence. However not all aspects of immunity decrease with age as ageing presents with systemic low grade chronic inflammation, characterised by elevated concentrations of mediators such as IL-6, TNFα and C Reactive protein (CRP). Inflammation is a strong predictor of morbidity and mortality, and chronic inflammation is known to be detrimental to a functioning immune system. Although the source of the inflammation is much discussed, the key cells which are believed to facilitate the inflammageing phenomenon are the monocytes and macrophages.

In this review we detail how macrophage and monocyte phenotype and function change with age. The impact of ageing on macrophages includes decreased phagocytosis and immune resolution, increased senescent-associated markers, increased inflammatory cytokine production, reduced autophagy, and a decrease in TLR expression. With monocytes there is an increase in circulating CD16+ monocytes, decreased type I IFN production, and decreased efferocytosis. In conclusion, we believe that monocytes and macrophages contribute to immunosenescence and inflammageing and as a result have an important role in defective immunity with age.

Introduction

Ageing populations are becoming a global trend [1], however increasing lifespan is outstripping health-span. This results in people living longer with chronic health conditions adversely impacting on quality of life. Older adults are at increased risk of hospitalisation and death from primary infections such as influenza [2], reactivation of latent infections such as shingles caused by Varicella-Zoster virus (VZV) [3], and are often living with chronic inflammatory diseases such as type 2 diabetes and rheumatoid arthritis. Although four vaccinations (Influenza, tetanus-reduced diphtheria-acellular pertussis [TdaP], Pneumococcal, and Herpes Zoster) are recommended for older individuals (>65 years) in the UK, vaccine efficacy decreases significantly with age [[4], [5], [6]].

All these age-related changes suggest that there are alterations in immunity which result in poorer antigen-specific immune responses and worse vaccine efficacy. To date the majority of the research has focussed on the adaptive immune system which has been reviewed extensively [7,8]. Although T and B cell changes are important in ageing, there is clearly also a role for innate immune cells. In this review we discuss age-related inflammation and how monocytes and macrophages contribute to these inflammatory processes. We then focus on what defines monocytes and macrophages, then what changes occur in these cells with age, and how this underlies diseases commonly associated with ageing.

Ageing is arguably primarily characterised by the accumulation of cells which have undergone the process of permanent cell cycle arrest, termed senescence [9]. Senescence can occur in all cells in the body, meaning that all tissues can contain senescent cells. Structural stromal cells, such as fibroblasts, show high levels of senescence with age. In the immune system, senescence has been shown in multiple cell types including macrophages and T cells [[10], [11], [12]]. However there is evidence, certainly in T cells, that what has been defined as senescence can be reversed with the addition of p38 MAP kinase inhibitors, begging the question if this is proper senescence or indeed if senescence is not always a state of permanent cell cycle arrest [12]. Senescence occurs as a result of irreparable cellular insults, such as excessive DNA damage, telomere erosion, or oxidative stress [13]. Senescent stromal cells do not divide and are apoptosis resistant [14]. They can be characterized by the expression of the CDK inhibitors p16INK4A and/or p21, telomere associated γH2AX foci and/or β-galactosidase expression. However, there is no single definitive marker of senescence and this subject has been reviewed extensively previously [13].

Systemic increases in senescent cell populations are closely linked to age-related pathology and inflammageing, which is the chronic low-grade inflammation observed with age in humans [15]. Senescent cells themselves secrete a raft of inflammatory mediators, termed the senescence associated secretory phenotype (SASP) [16]. The SASP can drive paracrine senescence perpetuating an increasingly senescent and inflammatory tissue environment [17]. Importantly, while the SASP is a profound source of inflammatory mediators, it does not encompass all mediators that are increased with age.

Inflammageing is characterised by an increase in circulating inflammatory mediators such as C Reactive protein (CRP), Interleukin (IL)-6 and Tumour Necrosis Factor (TNF)α [18]. Although acute inflammation is important for clearance of infection or facilitating wound healing, it is becoming increasingly clear that chronic inflammation is detrimental to a functioning immune response and health of the individual. Indeed, older people who have elevated circulating IL-6, CRP, TNFα, IL-1β or inflammasome-related genes have higher chance of all-cause mortality [[19], [20], [21]]. Conversely, lower levels of inflammatory cytokines in the peripheral blood correlate with good health outcomes, longevity, and reduced risk of death of older adults [22]. Not all older people age similarly - one such example is frailty, which is the individual’s biological age rather than chronological, and is considered to be an excellent guide for establishing the health of the individual. Inflammation is a strong predictor for frailty, and those older individuals who are most frail have highest levels of circulating CRP, IL-6 and IL-8 [23]. In addition, excessive inflammation has been shown to reduce vaccine efficacy [24,25], antigen-specific immunity [26] and increased immunoregulatory mechanisms to combat the increased inflammation [27].

The source of the inflammatory cytokine production during ageing is believed to be multi-factorial. SASP is an obvious contributor to this, but additional mechanisms have been proposed. Geriatric mice have been shown to have increased gut permeability which results in bacterial lipopolysaccharide (LPS) leakage into the blood stream and activation of mononuclear phagocytes via binding to Toll-like receptor (TLR)4 [28,29]. Older adults exhibit increased visceral adiposity; visceral fat is an inflammatory site as infiltrating immune cells, including mononuclear phagocytes, secrete a raft of inflammatory mediators [30]. Additionally, aged mice have elevated damage-associated molecular patterns (DAMPs), suggesting that human ageing may also lead to increased DAMP production [31]. DAMPS bind to a range of pattern recognition receptors (PRRs) on innate cells leading to a cascade of inflammatory cytokine production. Finally, the most recent proposed mechanism for increased inflammation with age is a failure of inflammatory resolution in older adults. The onset of inflammation is a highly active process, involving multiple cell types and mediators. We now appreciate that switching off inflammation is an equally involved process with distinct signalling and effector pathways all of which impact downstream immune responses [32]. We recently showed that although the onset of inflammation is similar between old and young, the resolution of inflammation was defective in older people leading to a prolonged inflammatory response [33]. Mononuclear phagocytes, consisting of monocytes and macrophages, were unable to engulf apoptotic immune cells following an inflammatory insult. This resulted in an accumulation of apoptotic cells, cellular debris, and mononuclear phagocytes that did not switch to a pro-resolution phenotype. Ultimately this kind of mechanism, of failed resolution, might underlie chronic inflammation such as that seen in aged people [33].

When Franceschi and colleagues coined the term inflammageing in 2000 [15], they suggested the root of age-related chronic inflammation was chronic activation of the macrophage. Whilst more recent data suggests that macrophages are not the sole source of inflammageing, it is clear that monocytes and macrophages are the central component in initiating the phenomenon. Although the effect of ageing on monocyte and macrophages has been studied and will be discussed in detail in this review, there are clearly facets of ageing in this context that are poorly understood. The focus of this review is an overview of the current knowledge of the impact of ageing on monocytes and macrophages, and how these cells can contribute to the inflammageing. In addition, this review will highlight areas of monocyte and macrophage biology where more research is required.

Section snippets

Macrophage phenotype and function

Macrophages are tissue resident cells known for phagocytosis, their name being derived from Greek meaning “big eaters”, first coined by Eli Metchnikoff in the late 19th century. He observed this population of cells in starfish larvae which had been pierced by tiny thorns going on to show that macrophages and the process of phagocytosis formed the “essence” of inflammation [34]. However, even following Metchnikoff’s Nobel prize in 1908 [35], the macrophage had long been undervalued and

Monocytes

Here follows a discussion of what is known with regards to monocytes during ageing. Ageing results in a plethora of phenotypic and functional changes in monocyte populations. These will be discussed in turn and are summarised in Fig. 2.

Future perspectives

Although many studies have been performed to look at the effects of age on monocyte and macrophage function, there are still many unknowns within the field of ageing. Macrophage ontogeny experiments are carried out in young mouse models, so there is a lack of data on if the origin of macrophage populations changes as we reach advanced age. We do not know whether there is a change in the monocyte contribution to the macrophage pool with advanced age. Also we do not know how age influences

Funding

This work was funded by a Barts Charity Lectureship (MGU045 to ESC).

Declaration of Competing Interest

The authors declare that they have no competing interests related to this work.

References (148)

  • Y. Arai et al.

    Inflammation, but not telomere length, predicts successful ageing at extreme old age: a longitudinal study of semi-supercentenarians

    EBioMedicine

    (2015)
  • M. Vukmanovic-Stejic et al.

    Enhancement of cutaneous immunity during aging by blocking p38 mitogen-activated protein (MAP) kinase-induced inflammation

    J. Allergy Clin. Immunol.

    (2018)
  • E.S. Chambers et al.

    Can blocking inflammation enhance immunity during aging?

    J. Allergy Clin. Immunol.

    (2020)
  • N. Feldman et al.

    DAMPs as mediators of sterile inflammation in aging-related pathologies

    Ageing Res. Rev.

    (2015)
  • K.T. Feehan et al.

    Is resolution the end of inflammation?

    Trends Mol. Med.

    (2019)
  • C. Bleriot et al.

    Determinants of resident tissue macrophage identity and function

    Immunity

    (2020)
  • S. Morioka et al.

    Living on the edge: efferocytosis at the interface of homeostasis and pathology

    Immunity

    (2019)
  • A. Mantovani et al.

    Macrophage polarization comes of age

    Immunity

    (2005)
  • S. Gordon et al.

    Alternative activation of macrophages: mechanism and functions

    Immunity

    (2010)
  • J. Bystrom et al.

    Resolution-phase macrophages possess a unique inflammatory phenotype that is controlled by cAMP

    Blood.

    (2008)
  • P.J. Murray et al.

    Macrophage activation and polarization: nomenclature and experimental guidelines

    Immunity

    (2014)
  • J. Newson et al.

    Inflammatory resolution triggers a prolonged phase of immune suppression through COX-1/mPGES-1-Derived prostaglandin E2

    Cell Rep.

    (2017)
  • J. Newson et al.

    Resolution of acute inflammation bridges the gap between innate and adaptive immunity

    Blood

    (2014)
  • N. McGovern et al.

    Human dermal CD14(+) cells are a transient population of monocyte-derived macrophages

    Immunity

    (2014)
  • T. Ogawa et al.

    Age-related changes of human bone marrow: a histometric estimation of proliferative cells, apoptotic cells, T cells, B cells and macrophages

    Mech. Ageing Dev.

    (2000)
  • S.L. Patterson

    Immune dysregulation and cognitive vulnerability in the aging brain: interactions of microglia, IL-1beta, BDNF and synaptic plasticity

    Neuropharmacology

    (2015)
  • R.M. Barrientos et al.

    Time course of hippocampal IL-1 beta and memory consolidation impairments in aging rats following peripheral infection

    Brain Behav. Immun.

    (2009)
  • Y. Huang et al.

    Exaggerated sickness behavior and brain proinflammatory cytokine expression in aged mice in response to intracerebroventricular lipopolysaccharide

    Neurobiol. Aging

    (2008)
  • A.M. Wynne et al.

    Protracted downregulation of CX3CR1 on microglia of aged mice after lipopolysaccharide challenge

    Brain Behav. Immun.

    (2010)
  • L.J. Hickson et al.

    Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease

    EBioMedicine

    (2019)
  • C. Cudejko et al.

    p16INK4a deficiency promotes IL-4-induced polarization and inhibits proinflammatory signaling in macrophages

    Blood

    (2011)
  • K.J. Claycombe et al.

    Ceramide mediates age-associated increase in macrophage cyclooxygenase-2 expression

    J. Biol. Chem.

    (2002)
  • M.E. Swift et al.

    Age-related alterations in the inflammatory response to dermal injury

    J. Invest. Dermatol.

    (2001)
  • P. Mancuso et al.

    Evaluation of phagocytosis and arachidonate metabolism by alveolar macrophages and recruited neutrophils from F344xBN rats of different ages

    Mech. Ageing Dev.

    (2001)
  • Y. Kang et al.

    Telomere dysfunction disturbs macrophage mitochondrial metabolism and the NLRP3 inflammasome through the PGC-1alpha/TNFAIP3 Axis

    Cell Rep.

    (2018)
  • D.A. Leon

    Trends in European life expectancy: a salutary view

    Int. J. Epidemiol.

    (2011)
  • D.M. Fleming et al.

    The impact of influenza on the health and health care utilisation of elderly people

    Vaccine

    (2005)
  • B. Weinberger et al.

    Biology of immune responses to vaccines in elderly persons

    Clin. Infect. Dis.

    (2008)
  • S. Ma et al.

    Cell dysfunction associated with aging and autoimmune diseases

    Front. Immunol.

    (2019)
  • B.I. Pereira et al.

    Senescent cells evade immune clearance via HLA-E-mediated NK and CD8(+) T cell inhibition

    Nat. Commun.

    (2019)
  • D. Di Mitri et al.

    Reversible senescence in human CD4+CD45RA+CD27- memory T cells

    J. Immunol.

    (2011)
  • B.G. Childs et al.

    Senescence and apoptosis: dueling or complementary cell fates?

    EMBO Rep.

    (2014)
  • C. Franceschi et al.

    Inflamm-aging. An evolutionary perspective on immunosenescence

    Ann. N. Y. Acad. Sci.

    (2000)
  • J.C. Acosta et al.

    A complex secretory program orchestrated by the inflammasome controls paracrine senescence

    Nat. Cell Biol.

    (2013)
  • H. Bruunsgaard et al.

    Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people

    Clin. Exp. Immunol.

    (2003)
  • D. Furman et al.

    Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states

    Nat. Med.

    (2017)
  • S. Giovannini et al.

    Interleukin-6, C-reactive protein, and tumor necrosis factor-alpha as predictors of mortality in frail, community-living elderly individuals

    J. Am. Geriatr. Soc.

    (2011)
  • A. Parmigiani et al.

    Impaired antibody response to influenza vaccine in HIV-infected and uninfected aging women is associated with immune activation and inflammation

    PLoS One

    (2013)
  • E. Muyanja et al.

    Immune activation alters cellular and humoral responses to yellow fever 17D vaccine

    J. Clin. Invest.

    (2014)
  • N. Thevaranjan et al.

    Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction

    Cell Host Microbe

    (2017)
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