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Microglial priming in neurodegenerative disease

Key Points

  • Microglia are involved in the communication of systemic inflammation to the brain

  • Microglia become primed by systemic inflammation or neurodegeneration

  • The exaggerated response of primed microglia to systemic inflammation contributes to the pathogenesis of neurodegenerative disease

  • Modulation of systemic inflammation offers novel strategies in the prevention and therapy of neurodegenerative disease

Abstract

Under physiological conditions, the number and function of microglia—the resident macrophages of the CNS—is tightly controlled by the local microenvironment. In response to neurodegeneration and the accumulation of abnormally folded proteins, however, microglia multiply and adopt an activated state—a process referred to as priming. Studies using preclinical animal models have shown that priming of microglia is driven by changes in their microenvironment and the release of molecules that drive their proliferation. Priming makes the microglia susceptible to a secondary inflammatory stimulus, which can then trigger an exaggerated inflammatory response. The secondary stimulus can arise within the CNS, but in elderly individuals, the secondary stimulus most commonly arises from a systemic disease with an inflammatory component. The concept of microglial priming, and the subsequent exaggerated response of these cells to secondary systemic inflammation, opens the way to treat neurodegenerative diseases by targeting systemic disease or interrupting the signalling pathways that mediate the CNS response to systemic inflammation. Both lifestyle changes and pharmacological therapies could, therefore, provide efficient means to slow down or halt neurodegeneration.

Introduction

The adjectives typically used to describe the appearance of microglia, the resident macrophages of the CNS (Box 1), in the absence of disease—downregulated, quiescent, resting, and so forth—reflect the fact that their numbers and activity are normally tightly controlled. Indeed, the influence of the molecular microenvironment of the brain on microglia is both profound and remarkable.

Resident macrophage populations in other tissues have highly variable protein expression profiles, but those of microglia are strikingly consistent. Although some subtle differences have been reported between microglia from different regions of the mouse brain, the uniformity of their repertoire is more noteworthy than the differences.1 Moreover, microglia express much lower levels of cell surface and cytoplasmic molecules than do other types of tissue macrophages:2 a microarray study demonstrated that microglia express several hundred fewer mRNA types than other tissue macrophages.3 This suppression of microglial activity involves not only soluble molecules expressed in the CNS, such as transforming growth factor β (TGF-β), but also a wide range of molecules expressed on the surface of neurons, which act as ligands for receptors on microglia (Box 2).

The tight regulation of microglia by molecular factors in the CNS might have evolved because microglia have the potential to damage brain tissue, which has limited capacity for regeneration and repair. Even in the downregulated state, however, microglia can monitor and respond to subtle changes in their local environment by constant movement of large cell processes, as well as palpation of the surfaces of adjacent neurons and glia by filopodia.4 Microglia have, therefore, been suggested to have a role in monitoring the health status of neurons and synapses within their territory by making brief contact with them through their processes,5,6 although only a small percentage of synapses are in contact with microglia at any given moment.7 The influence of internal environmental factors (such as systemic inflammatory disease) and external environmental factors (such as infection) on the CNS is transduced by the immune system into the release of cytokines, chemokines and other inflammatory mediators, which in turn affect humoral and neural pathways that convey these signals to the brain (reviewed elsewhere).8,9

This Review highlights the important role of macrophages and microglia in conveying signals about systemic inflammation to neurons, and the subsequent involvement of these cells in metabolic and behavioural changes associated with systemic inflammation. We discuss the concept that microglia respond to pathological changes in the CNS by becoming primed—that is, becoming more susceptible to activation—and that systemic inflammation affects these primed microglia, possibly contributing to disease progression in chronic neurodegenerative diseases.10,11

Microglial activation

Almost any disturbance of homeostasis in the CNS microenvironment can trigger activation of microglia, a process characterized by morphological changes and upregulation of a spectrum of intracellular molecules and surface antigens. Activated microglia can have diverse expression profiles, with the capacity to synthesize a broad spectrum of both proinflammatory and anti-inflammatory cytokines and other molecular mediators. In accordance with the distinctions proposed for 'cytotoxic' and 'repair' subpopulations of macrophages in other organs, activated microglia in the CNS are commonly referred to as M1-like or M2-like.12 However, this distinction is often overly simplistic: in a number of disease states, the range of cytokines and antigens expressed by activated microglia cut across the simple M1 and M2 categories.13,14 Moreover, attempts to categorize microglia on the basis of their expression of a very limited number of cytokines or other markers can lead to artificial distinctions that are of little use in understanding the true contributions of these cells to the pathogenesis of CNS diseases.

To explore whether local subpopulations of microglia exist, local injections of lipopolysaccharide (a bacterial cell wall component) into the CNS parenchyma have been used to mimic infection.15 The different profiles of cytokines produced by individual microglia within the region of injection after lipopolysaccharide challenge has been interpreted as evidence for the presence of microglial subtypes, but an alternative explanation is that lipopolysaccharide challenge simply does not induce transcription of a uniform profile of cytokine genes, even in phenotypically homogeneous microglia, in line with the results of microarray studies of clonal mouse RAW264 macrophages.16

Microglial priming

The phenomenon

Microglial priming is an exaggerated or heightened microglial response—much stronger than that observed in stimulus-naive microglia—to a second inflammatory stimulus (Figure 1). Currently, the notion that microglia are primed remains operationally defined: no clear or unique descriptors of primed microglia have been defined to date, although it is apparent that changes in morphology, upregulation of cell surface antigens and an increase in numbers of microglia are all associated with priming.

Figure 1: Effects of systemic inflammation on microglia.
figure1

a | In the absence of disease, microglia use motile processes to survey the parenchyma, and are kept in the quiescent state by regulatory factors in the brain parenchymal microenvironment and inhibitory ligands expressed on the surface of neurons. b | Following an initial systemic inflammatory stimulus, cytokines and other inflammatory mediators in the blood signal to receptors on cerebral endothelial cells, which in turn signal to perivascular macrophages and subsequently to microglia. These stimuli transiently activate microglia, leading to release of cytokines and probably other molecules in the brain that induce sickness behaviours.8 c | During chronic neurodegeneration, neurotoxic misfolded proteins and debris from dysfunctional or dying neurons accumulate. The resulting loss of inhibitory neuronal ligands and increase in neurodegenerative components leads to activation of microglia, indicated by altered morphology, increased proliferation and upregulation of cell surface molecules. Perivascular macrophage numbers also increase. d | In the setting of chronic neurodegeneration, the effect of a systemic inflammatory stimulus on the CNS is amplified owing to increased numbers of perivascular macrophages and microglia, as well as the primed state of microglia. The resulting exaggerated release of cytokines and other inflammatory mediators leads to neurotoxicity.

PowerPoint slide

The phenomenon of microglial priming was first described in the brains of animals with prion disease that were subjected to challenge with mimetics of systemic infection, such as lipopolysaccharide or polyinosinic–polycytidylic acid (poly I:C17,18,19,20), but has now been observed in diverse conditions associated with chronic neurodegeneration. For example, in animal models of Alzheimer disease (AD) and Parkinson disease (PD),14,21 systemic inflammatory challenge generates an exaggerated immune response in the CNS that is mediated by the local innate immune system. Whether different patterns of priming—giving rise to different phenotypes and molecular signatures—result from different forms of neurodegeneration or different systemic inflammatory stimuli remains an open question. The sequence of neurodegeneration and the role of systemic inflammation or other secondary stimuli could also influence the priming pattern.

Environmental signals communicated to a healthy CNS; for example, a transient peripheral infection22 or chronic exposure to low levels of infectious pathogens (that is, below those needed to cause clinical signs), can not only activate but also prime the microglia.23 Systemic inflammation may also lead to an exaggerated response to an acute brain injury, such as an ischaemic insult.24 Protracted exposure of tissue macrophages to very low levels of lipopolysaccharide induces priming rather than tolerance to lipopolysaccharide,25 which is potentially of particular importance in the context of PD: lipopolysaccharide may escape to the systemic circulation from the bowel in individuals with constipation,26 and since patients with PD are susceptible to constipation, increased systemic exposure to lipopolysaccharide might further exacerbate the neurodegenerative process through induction of microglial priming.27

The mechanisms of priming

As discussed above, a major element in regulation of the microglial phenotype is the molecular composition of the CNS microenvironment. Neuronal damage or degeneration leads to loss or downregulation of neuronal ligands that bind to inhibitory receptors on the microglia (Box 2), thereby releasing microglia from inhibition. In addition to reduced microglial inhibition, microglia can be directly activated by the accumulation of misfolded proteins in disorders such as AD. In both acute and chronic neurodegenerative conditions, the injury to neurons and glia can lead to microglial activation. Some systemic events could also be protective: for example, parasite infections in individuals with multiple sclerosis ameliorate the disease course,28 in contrast to viral infections, which can trigger relapses.29

Priming of macrophages following exposure to IFN-γ and secondary challenge with lipopolysaccharide has been studied extensively in vitro;30 however, other molecules expressed in the degenerating or injured brain, such as CSF-131 and C-C motif chemokine 2 (CCL2),32,33 can also prime microglia. Prior exposure of macrophages to these molecules leads to a more robust response to a secondary stimulus. CSF-1 binds and activates CSF-1R, which is also a receptor for IL-34,34,35 and both CSF-1R and IL-34 drive microglial proliferation.36 CCL2 also promotes microglial proliferation, although to a lesser extent than CSF-1R and IL-34, and perhaps indirectly.37 The intimate relationship between microglial priming and proliferation is potentially important, because both changes are commonly observed in neurodegenerative disorders, and both the primed state and the increased numbers of microglia contribute to the generation of an exaggerated response in the brain to microglial sensing of systemic inflammation.

The consequences of priming

In mice, inflammatory challenge in utero has been demonstrated to drive amyloid deposition in the adult brain, raising many interesting questions regarding the potential influence of early-life events on neurodegenerative disease in later life.38 In rodents, a systemic inflammatory challenge in the presence of primed microglia leads to fever and exaggerated expression of sickness behaviours (that is, adaptive changes in behaviour that aid recovery), including loss of activity and anorexia. These changes are associated with increased synthesis of cytokines such as IL-1, tumour necrosis factor (TNF) and IL-6, as well as nitric oxide, in the brain.17,18,19 The increased or altered inflammatory response may also lead to increased neuronal loss and accelerated disease progression. Multiple systemic challenges with poly I:C—mimicking repeated viral infections—in murine models of prion disease lead to an acute decline in motor performance at each challenge, and a residual decrement in motor co-ordination and strength in particular, contributing to the acceleration of disease progression.20

The concept of microglial priming thus provides a cellular and molecular pathway by which systemic inflammation might contribute to the progression of chronic neurodegenerative diseases. In addition to increased expression of cytokines that can damage neurons, primed microglia respond to further stimulation by altering their receptor repertoires in ways that might have important consequences. In mice with chronic neurodegenerative disease, for example, systemic inflammatory challenge increases the expression of Fc-type immunoglobulin receptors in the microglia, with an effect size that is many times greater than the influence of either neurodegenerative disease or systemic inflammation alone.39 The increased expression of Fc receptors in the microglia leads to a striking shift towards a proinflammatory state. Although IgG is not generally thought to enter the brain parenchyma, the blood–brain barrier (BBB) is apparently not entirely impenetrable to IgG. Consequently, treatment of disorders such as AD with immunotherapy, which encourages amyloid plaque removal through binding of antibodies to the plaques,40 carries a risk of bystander tissue damage mediated by Fc-receptor-dependent activation of primed microglia and the resulting inflammation.39 Rapidly accumulating evidence from preclinical studies shows that microglia priming and the subsequent inflammatory response lead to exacerbated tissue damage in animal models of prion disease,14 AD,41 PD,42 stroke24 and multiple sclerosis.43

From systemic inflammation to brain

The molecular pathways by which systemic inflammation leads to CNS inflammation and sickness behaviours have been most extensively studied in rodent models, using either a peripheral challenge with lipopolysaccharide or administration of the proinflammatory cytokines IL-1β, IL-6 and TNF, either alone or in combination.8,9 However, sensitivity to lipopolysaccharide is much higher in humans than it is in rodents,44 and the doses of lipopolysaccharide given in rodents are 1,000–10,000 times higher than the doses that would induce septic shock in humans, meaning that the applicability of results obtained in these models to humans is questionable.45,46 However, the results of most studies support the notion that systemic inflammation can result in microglial activation. For example, peripheral challenge using low doses of lipopolysaccharide is sufficient to induce microglial activation and sickness behaviours in both humans and nonhuman primates.47,48,49

Functional MRI studies of healthy human volunteers have shown that vaccination with a low dose of Salmonella typhi endotoxin can trigger a notable increase in systemic levels of IL-6, slowed reaction times, increased neuronal activity in the substantia nigra,47 and lowered mood accompanied with increased activity in the anterior cingulate cortex.48 In line with the systemic inflammation–neuroinflammation model, the results of a PET imaging study in nonhuman primates that used the translocator protein (TSPO) ligand 11C-PBR28 (a marker of microglial activation) demonstrated that intravenous administration of low-dose lipopolysaccharide gave rise to increased serum levels of IL-1β and IL-6, both of which correlated positively with increased binding of 11C-PBR28, indicating increased microglial activation.49 Another PET imaging study in humans with chronic systemic inflammatory conditions (atherosclerosis, diabetes mellitus or smoking-related disease) using a different TSPO ligand, 11C-PK11195, showed that, in keeping with the results observed in rodent models, mildly elevated serum C-reactive protein and IL-6 levels in the absence of any evidence of acute infection were also associated with increased microglial activation.50

Animal models have further elucidated the link between endocrine function and both CNS and systemic inflammation. Indeed, inflammation within the hypothalamus—an area critical for energy homeostasis51—contributes to a number of chronic systemic inflammatory conditions associated with ageing (such as hypertension, obesity and diabetes mellitus). The systemic effects seem to be mediated by increased production of nuclear factor κB (NF-κB),52 which is first observed in the microglia, but later spreads to neurons.53 Interestingly, NF-κB also inhibits production of gonadotrophin-releasing hormone, which promotes neurogenesis and ameliorates age-related cognitive decline.53 Findings from both humans and animal models of obesity support the idea that a high-fat diet and obesity are associated with neuronal damage in the hypothalamus.51 Age-related activation of microglial cells within the hypothalamus could, therefore, partly explain the relationships between chronic systemic inflammatory conditions, such as atherosclerosis,54 obesity55 and diabetes,56 and the development of age-related neurodegenerative disease.

Microglial dysfunction and CNS disease

In humans, rare mutations in the genes encoding microglial receptors have devastating consequences. Mutations in either TREM2 (which encodes triggering receptor expressed on myeloid cells 2) or TYROBP (which encodes TYRO protein tyrosine kinase-binding protein, an adaptor protein also known as DAP12) lead to Nasu–Hakola disease, which is also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy.57 The CNS pathology in Nasu–Hakola disease is characterized by severe disruption of cortical white matter tracts and development of dementia.58 Mutations in CSF1R, which codes for macrophage colony-stimulating factor 1 receptor (a molecule essential for the development and maintenance of cells of the macrophage lineage)59 also lead to devastating pathology in the white matter associated with progressive dementia, termed hereditary diffuse leukoencephalopathy with spheroids. The time of disease onset and severity depends on the nature of the mutation (point mutation versus deletion).60 The profound effects of these mutations on white matter integrity (along with the fact that, in the human brain, more microglia reside in white matter tracts than in the grey matter) suggest that microglia have a role in myelin or axonal homeostasis that is yet to be discovered.

Microglia and Alzheimer disease

Ageing is the main risk factor for AD, and is accompanied by chronic, low-grade systemic upregulation of the proinflammatory T helper type 1 response and a relative decline in the anti-inflammatory T helper type 2 response.61 This shift towards an inflammatory state is hypothesized to be caused by age-related factors that result in an imbalance between proinflammatory and anti-inflammatory networks. One important age-related modifying factor is endocrine dyscrasia: the resulting reduction in sex steroid levels is associated with a shift towards a systemic proinflammatory state and an increased risk of developing the pathological changes observed in AD.62,63 In the ageing human brain, widespread upregulation of genes involved in the innate immune response has been observed.64

Systemic inflammation

If systemic inflammation affects the human brain in a manner comparable to that described in preclinical models, we might expect to find evidence suggesting that the microglial phenotype in the brains of patients with AD is influenced by systemic infection or disease. Unfortunately, despite the large (and increasing) number of postmortem studies that have shown neuroinflammation in the brains of these individuals, the donors' systemic diseases have seldom been documented in the material reported in neuropathological studies. Severe systemic inflammation, such as sepsis, has been shown to affect the microglial phenotype, although this study assessed a very limited number of biomarkers for this phenotype.65 A subsequent study of brains from patients with either mild or late-stage AD examined whether the inflammatory response in the brain was M1-like or M2-like, and also sought to find serum markers that would predict or be associated with these two different phenotypes.66 Interestingly, some brains showed an M1 bias and others had an M2 bias; the M1-like state was associated with raised serum levels of CCL3 and the M2-like state with raised serum levels of IL-1 receptor antagonist.66 Although this study was based on a fairly small number of brain samples, the results highlight both the variability in the brain inflammatory response associated with AD and the potential relationship between neuroinflammation and systemic inflammatory profiles, which (perhaps not surprisingly) also show considerable variability in cross-sectional studies.67

Awareness is growing that the presence of systemic diseases or impaired physiological functioning, such as physical frailty,68 chronic kidney disease69 or type 2 diabetes mellitus,70 are associated with cognitive decline. In the ageing population, a significant proportion of individuals has more than one systemic disease,71 meaning that systemic inflammation has high clinical importance as a risk factor for AD. Our research group has shown that systemic inflammation and acute infections are associated with an increased rate of cognitive decline72 and exacerbation of the symptoms of sickness73 in patients with AD.

Genetic risk factors

Apolipoprotein E allele ε4 (APOE*ε4) is the best-established genetic risk factor for AD. Apo-E has an important role in lipid transport; however, early studies also highlighted the influence of APOE*ε4 on the degree of microglial activation in response to amyloid-β (Aβ) deposition,74 and associations have been reported between APOE*ε4 and poor outcomes in a number of CNS and systemic infections.75,76,77 The possibility that other common genetic polymorphisms, albeit with smaller effect sizes, could also affect immune regulation and thereby the development of AD is now becoming increasingly established.

The first two large-scale genome-wide association studies that aimed to identify genetic risk factors for AD78,79 both identified polymorphisms in the genes encoding complement receptor 1 (CR1) and clusterin. CR1 has binding sites for complement factors C3b and C4b. Like Apo-E, clusterin is involved in lipid transport, but has also been hypothesized to influence receptor-mediated clearance of Aβ from the brain by microglial endocytosis.80 Combination of these two studies to analyse common, functionally related molecular pathways revealed a number of important pathways involved in innate immunity.81 Two subsequent studies82,83 identified five additional genes (CD33, the MS4A6–MS4A4 cluster, ABCA7, CD2AP and EPHA1), the products of which are all postulated to be involved in immune system activation. Myeloid cell surface antigen CD33 is expressed on monocytes and is associated with microglial activation.84 The MS4A6–MS4A4 cluster has marked sequence similarity to the gene encoding CD20, a B-lymphocyte cell surface molecule.85 ATP-binding cassette subfamily A member 7 is involved in macrophage phagocytosis,86 and CD2-associated protein is required for immune synapse formation.87 Ephrin type-A receptor 1 has no known brain-specific function, although it is expressed by CD4+ T lymphocytes.88

Other studies of genetic factors associated with late-onset AD have focused on the identification of rare genetic variants with large effect sizes. Two independent data sets have identified a rare missense mutation in TREM2, already described above, which gives rise to a threefold increase in the risk of AD.89,90 TREM2 is highly expressed on microglial cells and its expression suppresses proinflammatory cytokine production,91 suggesting that these variants confer a heightened risk of AD by increasing the proinflammatory response.

To conclude, a plethora of genetic studies show that inflammatory pathways have a key role in the development of late-onset AD. Importantly, the identified genes do not have associations with CNS inflammation alone; indeed, some show little evidence for a role in anything other than systemic inflammation.

Therapeutic interventions

Clinical trials of a wide range of anti-inflammatory agents that affect both peripheral inflammation and inflammation in the brain, including NSAIDs,92,93,94 rosiglitazone,95 statins96,97,98 and low-dose prednisone,99 have, to date, failed to slow down the progression of AD. A number of hypotheses have been put forward to explain these disappointing findings, including variable BBB permeability and inadequate suppression of key proinflammatory cytokines.92,93,94,95,96,97,98,99 Interest in the development of specific anti-cytokine agents that can cross the BBB is, therefore, increasing. However, treatment with existing anti-cytokine agents, such as anti-TNF agents, might also have beneficial effects in AD resulting from a dampening down of the systemic proinflammatory cytokine signal to the brain, which in turn reduces secondary microglial activation.

Interestingly, the incidence of AD seems to be reduced in patients who are long-term users of anti-inflammatory drugs such as statins,100 NSAIDs101,102,103 or TNF blockers,104 and in those who participate in exercise,105 which reduces proinflammatory drive.106 In these populations, the development of AD may be delayed as a result of the inhibitory effect of reduced proinflammatory drive on amyloid production,107 as well as a reduction in the detrimental effects of increased levels of proinflammatory cytokines on neuronal function. Our research group has speculated that the reason for the greater success of preventative strategies compared with therapeutic approaches is that early intervention (that is, before amyloid accumulates in the brain and priming of microglia is established) might be particularly suitable for peripherally or centrally acting agents that have only modest anti-inflammatory cytokine effects.

Conclusions

The evidence indicating that an innate immune response is involved in chronic neurodegenerative diseases is well-established, but the precise mechanisms by which systemic inflammation can contribute to disease onset and progression remain to be resolved. Ageing—the single biggest risk factor for the majority of such diseases—is associated with a decline in systemic physiological functioning and the accumulation of comorbidities such as diabetes, atherosclerosis and other systemic diseases. Emerging evidence supports the concept that microglia, primed by the accumulation of misfolded proteins and degeneration or dysfunction of neurons, act as the nexus of communication between age-related systemic comorbidities and the proinflammatory milieu associated with ageing. In turn, the exaggerated responses of primed microglia to these factors could lead to further neuronal dysfunction and degeneration. According to this hypothesis, treatment of systemic inflammation and disease could potentially delay or ameliorate the onset and progression of chronic neurodegeneration. Further longitudinal cohort studies that take a holistic approach to the physiological changes associated with ageing, systemic disease and inflammation, and assess integrated measures of cognition, mood, and other parameters of brain function, will be required to enable us to understand the factors that underlie healthy ageing, as well as those conferring a predisposition to—or resilience against—chronic neurodegenerative disease.

Review criteria

A search for original articles published between 2010 and 2014 and focusing on systemic inflammation was performed in MEDLINE and PubMed. The search terms used were “neurodegenerative disease”, “Alzheimer's disease”, “inflammation” and “systemic”, alone and in combination. All articles identified were English-language, full-text papers. We also searched the reference lists of identified articles for further relevant papers.

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Acknowledgements

The authors' research work is supported by grants from Alzheimer's Society and Alzheimer's Research Trust UK (V.H.P. and C.H.), and by funding from the Medical Research Council and Wellcome Trust (V.H.P.).

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V.H.P. and C.H. researched data for the article, wrote the article, and undertook reviewing and editing of the manuscript before submission.

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Correspondence to V. Hugh Perry.

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V.H.P. and C.H. have received an independent investigator grant from Pfizer to determine the safety and tolerability of etanercept in patients with Alzheimer disease.

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Perry, V., Holmes, C. Microglial priming in neurodegenerative disease. Nat Rev Neurol 10, 217–224 (2014). https://doi.org/10.1038/nrneurol.2014.38

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