RESUMEN
There is no satisfactory explanation for the sex-related differences in the incidence of many diseases and this is also true of Alzheimer's disease (AD), where females have a higher lifetime risk of developing the disease and make up about two thirds of the AD patient population. The importance of understanding the cause(s) that account for this disproportionate distribution cannot be overestimated, and is likely to be a significant factor in the search for therapeutic strategies that will combat the disease and, furthermore, potentially point to a sex-targeted approach to treatment. This review considers the literature in the context of what is known about the impact of sex on processes targeted by drugs that are in clinical trial for AD, and existing knowledge on differing responses of males and females to these drugs. Current knowledge strongly supports the view that trials should make assessing sex-related difference in responses a priority with a focus on exploring the sex-stratified treatments.
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Microglial phenotype changes in the aged brain, and also in neurodegenerative diseases, and it is generally accepted that these changes at least contribute to the inflammation that can have detrimental effects on brain health. Accumulating data have determined that there are multiple microglial activation states with consistent findings indicating that with stressors including age, a switch towards an inflammatory phenotype occurs. Among the changes that accompany this is a change in metabolism, whereby glycolysis is increased in microglia. Here, we asked whether sex impacted on the response of microglia to two stressors, interferon-γ + amyloid-ß (IFNγ + Aß) and age. The data show that IFNγ + Aß triggered cells from female mice to adopt a glycolytic phenotype. Metabolism was also altered with age; microglia from aged male mice responded by increasing oxidative phosphorylation, and microglial motility was preserved, contrasting with microglia from female mice where motility was compromised. We conclude that sex is a significant variable in the responses of microglia to stressors.
Asunto(s)
Interferón gamma , Microglía , Animales , Femenino , Masculino , Ratones , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Inflamación/metabolismo , Interferón gamma/metabolismo , Microglía/metabolismo , EnvejecimientoRESUMEN
Many studies implicate microglia in the pathogenesis of Alzheimer's disease (AD) but precisely how these cells make their impact has not been determined to date. One contributory factor is likely to be the enhanced production of inflammatory mediators and it is now known that microglia with this secretory phenotype exhibit other adaptations including in their morphology, function, and metabolism. AD, like many neurological disorders, demonstrates a sex bias and recent evidence indicates that the sexual dimorphism in microglial function, which has been recognized for many years in early development, persists into adulthood and aging. Here, we demonstrate sex-related differences in microglia from post mortem tissue of male and female AD patients and a marked increase in the number of dystrophic and rod-shaped microglia in tissue from female AD patients compared with males. Furthermore, there was an increase in iron-laden microglia in tissue from female AD patients and this has been reported to reflect mitochondrial changes. To address this further, we assessed changes in microglia from male and female APP/PS1 mice and demonstrate that iron accumulation in microglia is increased to a greater extent in tissue prepared from females compared with males. This was associated with altered expression of genes coding for proteins that modulate mitochondrial function. The findings suggest that sex-related differences in the severity and perhaps incidence of AD may, at least in part, arise from sexual dimorphism in microglia.
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One area of microglial biology that has been relatively neglected until recently is sex differences and this is in spite of the fact that sex is a risk factor in several diseases that are characterized by neuroinflammation and, by extension, microglial activation. Why these sex differences exist is not known but the panoply of differences extend to microglial number, genotype and phenotype. Significantly, several of these sex-related differences are also evident in health and change during life emphasizing the dynamic and plastic nature of microglia. This review will consider how age impacts on sex-related differences in microglia and ask whether the advancement of personalized medicine demands that a greater focus is placed on studying sex-related differences in microglia in Alzheimer's disease, Parkinson's disease and models of inflammatory stress and trauma in order to make true progress in dealing with these conditions.
RESUMEN
There is a striking sex-related difference in the prevalence of many neurodegenerative diseases, highlighting the need to consider whether treatments may exert sex-specific effects. A change in microglial activation state is a common feature of several neurodegenerative diseases and is considered to be a key factor in driving the inflammation that characterizes these conditions. Among the changes that have been described is a switch in microglial metabolism towards glycolysis which is associated with production of inflammatory mediators and reduced function. Marked sex-related differences in microglial number, phenotype and function have been described in late embryonic and early postnatal life in rodents and some reports suggest that sexual dimorphism extends into adulthood and age and, in models of Alzheimer's disease, the changes are more profound in microglia from female, compared with male, mice. Dimethyl fumarate (DMF) is a fumaric acid ester used in the treatment of psoriasis and relapsing remitting multiple sclerosis and, while its mechanism of action is unclear, it possesses anti-inflammatory and anti-oxidant properties and also impacts on cell metabolism. Here we treated 16-18-month-old female and male mice with DMF for 1 month and assessed its effect on microglia. The evidence indicates that it exerted sex-specific effects on microglial morphology and metabolism, reducing glycolysis only in microglia from female mice. The data suggest that this may result from its ability to inactivate glyceraldehyde-3-phosphate dehydrogenase (GAPDH).
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Dimetilfumarato , Esclerosis Múltiple Recurrente-Remitente , Animales , Dimetilfumarato/metabolismo , Femenino , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Masculino , Ratones , Microglía/metabolismo , Esclerosis Múltiple Recurrente-Remitente/metabolismoRESUMEN
Age and sex are major risk factors in Alzheimer's disease (AD) with a higher incidence of the disease in females. Neuroinflammation, which is a hallmark of AD, contributes to disease pathogenesis and is inexorably linked with inappropriate microglial activation and neurodegeneration. We investigated sex-related differences in microglia in APP/PS1 mice and in post-mortem tissue from AD patients. Changes in genes that are indicative of microglial activation were preferentially increased in cells from female APP/PS1 mice and cells from males and females were morphological, metabolically and functionally distinct. Microglia from female APP/PS1 mice were glycolytic and less phagocytic and associated with increased amyloidosis whereas microglia from males were amoeboid and this was also the case in post-mortem tissue from male AD patients, where plaque load was reduced. We propose that the sex-related differences in microglia are likely to explain, at least in part, the sexual dimorphism in AD.
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Enfermedad de Alzheimer/metabolismo , Microglía/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Femenino , Regulación de la Expresión Génica , Glucólisis , Humanos , Masculino , Ratones , Ratones Transgénicos , Microglía/patología , Factores SexualesRESUMEN
Neuroinflammation is now recognised as an important contributory factor in the progression of Alzheimer's disease and probably also in the early stages of the disease. It is likely that this derives largely from aberrant activation of microglia, the resident mononuclear phagocytes of the brain. These cells are responsible for physiological immune surveillance and clearance of pathogens in the central nervous system, but evidence indicates that in Alzheimer's disease, microglial function is compromised, and this contributes to the pathology. It is unclear what factors cause the inappropriate activation of the microglia in Alzheimer's disease, but one contributor may be infiltrating peripheral immune cells and these include macrophages and T cells. It has been suggested that both cell types modulate the phenotype of microglia, highlighting the importance of crosstalk between the innate and adaptive immune system in Alzheimer's disease. This review outlines our current knowledge of how cells of the peripheral immune system, specifically macrophages and T cells, may modulate microglial phenotype in the context of Alzheimer's disease and considers the impact on their function, especially phagocytic capacity.
RESUMEN
Microglial activation and neuroinflammatory changes are characteristic of the aged brain and contribute to age-related cognitive impairment. Exercise improves cognitive function in aged animals, perhaps because of a modulatory effect on microglial activation. Recent evidence indicates that inflammatory microglia are glycolytic, driven by an increase in 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), an enzyme that is described as the master regulator of glycolysis. Here we investigated whether microglia from aged animals exhibited a glycolytic signature and whether exercise exerted a modulatory effect on this metabolic profile. Young (4 month-old) and aged (18 month-old) mice were trained for 10 days on a treadmill. One day before sacrifice, animals were assessed in the novel object recognition and the object displacement tests. Animals were sacrificed after the last bout of exercise, microglial cells were isolated, cultured for 5 days and assessed for metabolic profile. Performance in both behavioural tests was impaired in sedentary aged animals and exercise attenuated this age-related effect. A significant increase in glycolysis, glycolytic capacity and PFKFB3 was observed in microglia from aged animals and exercise ameliorated these effects, while it also increased the phagocytic capacity of cells. The senescent markers, ß-galactosidase and p16INK4A, were increased in microglia from sedentary aged mice, and expression of these markers was significantly decreased by exercise. The data demonstrate that the exercise-related improved cognition is orchestrated by a normalization of the metabolic profile and functionality of microglia.
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Envejecimiento , Reprogramación Celular , Senescencia Celular , Microglía , Fosfofructoquinasa-2 , Condicionamiento Físico Animal , Animales , Encéfalo/metabolismo , Glucólisis , Ratones , Microglía/metabolismo , Fosfofructoquinasa-2/metabolismoRESUMEN
In the past few years it has become increasingly clear that an understanding of the interaction between metabolism and immune function can provide an insight into cellular responses to challenges. Significant progress has been made in terms of how macrophages are metabolically re-programmed in response to inflammatory stimuli but, to date, little emphasis has been placed on evaluating equivalent changes in microglia. The need to make progress is driven by the fact that, while microglial activation and the cell's ability to adopt an inflammatory phenotype is necessary to fulfil the neuroprotective function of the cell, persistent activation of microglia and the associated neuroinflammation is at the heart of several neurodegenerative diseases. Understanding the metabolic changes that accompany microglial responses may broaden our perspective on how dysfunction might arise and be tempered. This review will evaluate the current literature that addresses the interplay between inflammation and metabolic reprogramming in microglia, reflecting on the parallels that exist with macrophages. It will consider the changes that take place with age including those that have been reported in neurons and astrocytes with the development of non-invasive imaging techniques, and reflect on the literature that is currently available relating to metabolic reprogramming of microglia with age and in neurodegeneration. Finally it will consider the possibility that manipulating microglial metabolism may provide a valuable approach to modulating neuroinflammation.
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Enfermedad de Alzheimer/metabolismo , Astrocitos/metabolismo , Encéfalo/metabolismo , Glucólisis , Inflamación/metabolismo , Microglía/metabolismo , Neuronas/metabolismo , Enfermedad de Alzheimer/inmunología , Animales , Astrocitos/inmunología , Encéfalo/inmunología , Humanos , Inflamación/inmunología , Microglía/inmunología , Neuronas/inmunologíaRESUMEN
Inflammation and metabolism are intricately linked during inflammatory diseases in which activation of the nucleotide-binding domain-like receptors Family Pyrin Domain Containing 3 (NLRP3) inflammasome, an innate immune sensor, is critical. Several factors can activate the NLRP3 inflammasome, but the nature of the link between NLRP3 inflammasome activation and metabolism remains to be thoroughly explored. This study investigates whether the small molecule inhibitor of the NLRP3 inflammasome, MCC950, modulates the lipopolysaccharide (LPS) -and amyloid-ß (Aß)-induced metabolic phenotype and inflammatory signature in macrophages. LPS + Aß induced IL-1ß secretion, while pre-treatment with MCC950 inhibited this. LPS + Aß also upregulated IL-1ß mRNA and supernatant concentrations of TNFα, IL-6 and IL-10, however these changes were insensitive to MCC950, confirming that MCC950 specifically targets inflammasome activation in BMDMs. LPS + Aß increased glycolysis and the glycolytic enzyme, PFKFB3, and these effects were decreased by MCC950. These findings suggest that NLRP3 inflammasome activation may play a role in modulating glycolysis. To investigate this further, the effect of IL-1ß on glycolysis was assessed. IL-1ß stimulated glycolysis and PFKFB3, mimicking the effect of LPS + Aß and adding to the evidence that inflammasome activation impacts on metabolism. This contention was supported by the finding that the LPS + Aß-induced changes in glycolysis and PFKFB3 were attenuated in BMDMs from NLRP3-deficient and IL-1R1-deficient mice. Consistent with a key role for PFKFB3 is the finding that the PFKFB3 inhibitor, 3PO, attenuated the LPS + Aß-induced glycolysis. The data demonstrate that activation of the NLRP3 inflammasome, and the subsequent release of IL-1ß, play a key role in modulating glycolysis via PFKFB3. Reinstating metabolic homeostasis by targeting the NLRP3 inflammasome-PFKFB3 axis may provide a novel therapeutic target for treatment of acute and chronic disease.
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Glucólisis/efectos de los fármacos , Inflamasomas , Inflamación/inmunología , Macrófagos/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR , Fosfofructoquinasa-2/metabolismo , Péptidos beta-Amiloides , Animales , Células Cultivadas , Furanos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Indenos , Inflamasomas/antagonistas & inhibidores , Inflamasomas/fisiología , Inflamación/inducido químicamente , Interleucina-1beta/inmunología , Lipopolisacáridos , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/fisiología , Fosfofructoquinasa-2/antagonistas & inhibidores , Sulfonamidas , Sulfonas/farmacologíaRESUMEN
Among the changes that typify Alzheimer's disease (AD) are neuroinflammation and microglial activation, amyloid deposition perhaps resulting from compromised microglial function and iron accumulation. Data from Genome Wide Association Studies (GWAS) identified a number of gene variants that endow a significant risk of developing AD and several of these encode proteins expressed in microglia and proteins that are implicated in the immune response. This suggests that neuroinflammation and the accompanying microglial activation are likely to contribute to the pathogenesis of the disease. The trigger(s) leading to these changes remain to be identified. In this study, we set out to examine the link between the inflammatory, metabolic and iron-retentive signature of microglia in vitro and in transgenic mice that overexpress the amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1 mice), a commonly used animal model of AD. Stimulation of cultured microglia with interferon (IFN)γ and amyloid-ß (Aß) induced an inflammatory phenotype and switched the metabolic profile and iron handling of microglia so that the cells became glycolytic and iron retentive, and the phagocytic and chemotactic function of the cells was reduced. Analysis of APP/PS1 mice by magnetic resonance imaging (MRI) revealed genotype-related hypointense areas in the hippocampus consistent with iron deposition, and immunohistochemical analysis indicated that the iron accumulated in microglia, particularly in microglia that decorated Aß deposits. Isolated microglia prepared from APP/PS1 mice were characterized by a switch to a glycolytic and iron-retentive phenotype and phagocytosis of Aß was reduced in these cells. This evidence suggests that the switch to glycolysis in microglia may kick-start a cascade of events that ultimately leads to microglial dysfunction and Aß accumulation.
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Enfermedad de Alzheimer/metabolismo , Hierro/metabolismo , Microglía/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Encéfalo/patología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Hipocampo/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Presenilina-1/genética , Presenilina-1/metabolismoRESUMEN
The search for a blood-based biomarker that identifies Alzheimer's disease (AD) and can replace current invasive and expensive diagnostic tests, continues. The most extensively-examined peripheral marker is ß-amyloid (Aß) but the results are inconsistent across studies and do not reflect the changes that take place in the brain. Several studies have assessed possible proteomic signatures but with inconsistent findings, although increases in circulating inflammatory molecules are generally observed. Here, rather than focus on identifying changes in the circulation, we evaluated the effect of plasma from patients with mild cognitive impairment (MCI) and AD on the human monocyte-like cell line, THP-1 cells, and plasma from an AD mouse model on a mouse monocyte-macrophage cell line, J774.2 cells. Plasma from AD patients and the AD mouse model increased inflammatory molecules in the cells and these changes were accompanied by an increase in glycolysis. Interestingly, plasma from MCI patients exerted no significant effect on THP-1 cells. The possibility therefore exists that evaluating the effect of plasma on IL-8 and TNFα mRNA in THP-1 cells combined with analysis of glycolysis in these cells, may be the basis of an indicator that discriminates between AD and MCI and normal controls, but is unlikely to be useful in identifying early pathological changes.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/farmacología , Monocitos/metabolismo , Anciano , Péptidos beta-Amiloides/metabolismo , Animales , Quimiocina CXCL1/metabolismo , Citocinas/metabolismo , Femenino , Glucólisis , Humanos , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo II/metabolismo , Células THP-1RESUMEN
Potential associations between systemic inflammation and social support received by a sample of 120 older adults were examined here. Inflammatory markers, cognitive function, social support and psychosocial wellbeing were evaluated. A structural equation modelling approach was used to analyse the data. The model was a good fit χ1082=256.13 , p < 0.001; comparative fit index = 0.973; Tucker-Lewis Index = 0.962; root mean square error of approximation = 0.021; standardised root mean-square residual = 0.074). Chemokine levels were associated with increased age ( ß = 0.276), receipt of less social support from friends ( ß = -0.256) and body mass index ( ß = -0.256). Results are discussed in relation to social signal transduction theory.
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Envejecimiento/inmunología , Índice de Masa Corporal , Quimiocinas/sangre , Inflamación/sangre , Satisfacción Personal , Apoyo Social , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Inflamación/epidemiología , Masculino , Persona de Mediana Edad , Factores ProtectoresRESUMEN
BACKGROUND: Microglia are multifunctional cells that are primarily neuroprotective and a deficit in their functional integrity is likely to be a contributory factor in the deteriorating neuronal function that occurs with age and neurodegeneration. One aspect of microglial dysfunction is reduced phagocytosis, and this is believed to contribute to the accumulation of amyloid-ß (Aß) in Alzheimer's disease (AD). Therefore, improving phagocytosis should be beneficial in limiting the amyloidosis that characterises AD. METHODS: Here, we investigated whether an antibody that targets toll-like receptor (TLR)2 might attenuate the inflammatory and metabolic changes induced by lipopolysaccharide (LPS) and amyloid-ß. The impact on phagocytosis was assessed by immunohistochemistry. We evaluated the metabolic changes with the SeaHorse Extracellular Flux Analyser and studied the expression of key enzymes driving glycolysis by western blotting. For all experiments, statistical significance was determined by unpaired Student's t test and two-way analysis of variance (ANOVA). RESULTS: We have reported that, when exposed to an inflammatory stimulus, microglia switch their metabolism towards the metabolically- inefficient glycolysis; this potentially impacts on metabolically demanding functions like phagocytosis. Anti-TLR2 antibody increased phagocytosis of Aß in LPS + Aß-stimulated microglia and this was linked with the ability of the antibody to attenuate the LPS + Aß-triggered inflammasome activation. LPS + Aß increased glycolysis in microglia and increased the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)3, an enzyme that plays a key role in driving glycolysis; these effects were inhibited when cells were incubated with the anti-TLR2 antibody. The data also show that antibody treatment increased oxidative metabolism. CONCLUSIONS: Thus, microglia with an inflammatory phenotype, specifically cells in which the inflammasome is activated, are glycolytic; this may compromise the metabolic efficiency of microglia and thereby provide an explanation for the reduced phagocytic function of the cells. We propose that, by restoring oxidative metabolism and reducing inflammasome activation in microglia, phagocytic function is also restored.
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Péptidos beta-Amiloides/metabolismo , Anticuerpos/farmacología , Microglía/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Receptor Toll-Like 2/inmunología , Péptidos beta-Amiloides/farmacología , Animales , Animales Recién Nacidos , Arginasa/metabolismo , Proteínas de Unión al Calcio/metabolismo , Caspasa 1/metabolismo , Corteza Cerebral/citología , Citocinas/genética , Citocinas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/farmacología , Insecticidas/farmacología , Lipopolisacáridos/farmacología , Proteína 1 de la Membrana Asociada a los Lisosomas/metabolismo , Ratones , Proteínas de Microfilamentos/metabolismo , Microscopía Confocal , Rotenona/farmacologíaRESUMEN
Identification of a blood-based biomarker that can detect early cognitive decline presents a significant healthcare challenge. We prepared peripheral blood mononuclear cells (PBMCs) from individuals who had a poorer than predicted performance in their delayed recall performance on the Logical Memory II Subtest of the Wechsler Memory Scale (WMS) relative to their IQ estimated by the National Adult Reading Test (NART); we described these individuals as IQ-discrepant, compared with IQ-consistent, individuals. Stimulation with Aß + LPS increased production of TNFα to a greater extent in cells from IQ-discrepant, compared with IQ-consistent, individuals. This was associated with a shift towards glycolysis and the evidence indicates that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)3 plays a role in driving glycolysis. A similar shift towards glycolysis was observed in MDMs prepared from IQ-discrepant, compared with IQ-consistent, individuals. The important finding here is that we have established an increased sensitivity to Aßâ¯+â¯LPS stimulation in PBMCs from individuals that under-perform on a memory task, relative to their estimated premorbid IQ, which may be an indicator of early cognitive decline. This may be a useful tool in determining the presence of early cognitive dysfunction.
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Biomarcadores/sangre , Disfunción Cognitiva/metabolismo , Glucólisis , Inflamación/metabolismo , Leucocitos Mononucleares/metabolismo , Anciano , Células Cultivadas , Disfunción Cognitiva/diagnóstico , Diagnóstico Precoz , Femenino , Glucólisis/fisiología , Humanos , Inflamación/patología , Leucocitos Mononucleares/patología , Masculino , Memoria , Pruebas de Memoria y Aprendizaje , Persona de Mediana EdadRESUMEN
It is well established that infection has a significant detrimental effect on patients with Alzheimer's disease (AD), accelerating cognitive decline and, even in healthy ageing individuals, increasing amyloid-ß (Aß) accumulation in the brain. In animal models of AD infection can also cause damage, with evidence of increased neuroinflammation, amyloid pathology and deterioration of cognitive function. These changes are against a backdrop of an age- and AD-related increase in susceptibility to infection. Here we set out to determine whether FTY720, a molecule that binds sphingosine-1-phosphate (S1P) receptors and with known immunosuppressant effects mediating its therapeutic action in multiple sclerosis (MS), might modulate the impact of infection in a mouse model of AD. Transgenic mice that overexpress amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1 mice) and their littermates were/were not infected with Bordetella pertussis and were treated orally with FTY720 or vehicle beginning 3 days before infection. Infection increased astrocytic activation and enhanced blood brain barrier (BBB) permeability and these changes were attenuated in FTY720-treated B. pertussis-infected mice. Significantly, infection increased Aß containing plaques and soluble Aß and these infection-related changes were also attenuated in FTY720-treated B. pertussis-infected mice. The data suggest that this effect results from an FTY720-induced increase in Aß phagocytosis by astrocytes. FTY720 did not impact on genotype-related changes in the absence of an infection indicating that its potential usefulness is restricted to reducing the impact of acute inflammatory stimuli in AD.
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Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/patología , Astrocitos/efectos de los fármacos , Infecciones por Bordetella/complicaciones , Clorhidrato de Fingolimod/farmacología , Inmunosupresores/farmacología , Péptidos beta-Amiloides/efectos de los fármacos , Precursor de Proteína beta-Amiloide/genética , Animales , Astrocitos/metabolismo , Bordetella pertussis , Ratones , Ratones Transgénicos , Placa Amiloide/patología , Presenilina-1/genéticaRESUMEN
Th1 and Th17 cells have an established role in protective immunity to Bordetella pertussis, but this evidence is based largely on peripheral T cells. There is emerging evidence that local tissue-resident memory T (TRM) cells that accumulate in tissue following mucosal infection may be crucial for long-term immunity. In this study, we examined the role of respiratory CD4 TRM cells in immunity to B. pertussis Natural immunity to B. pertussis induced by infection is considered long lasting and effective at preventing reinfection. Consistent with this, we found that convalescent mice rapidly cleared the bacteria after reinfection. Furthermore, CD4 T cells with a TRM cell phenotype (CD44+CD62L-CD69+ or CD44+CD62L-CD69+CD103+) accumulated in the lungs of mice during infection with B. pertussis and significantly expanded through local proliferation following reinfection. These CD4 TRM cells were B. pertussis specific and secreted IL-17 or IL-17 and IFN-γ. Treatment of mice with FTY720, which prevented migration of T and B cells from lymph nodes to the circulation, significantly exacerbated B. pertussis infection. This was associated with significantly reduced infiltration of central memory T cells and B cells into the lungs. However, the local expansion of TRM cells and the associated rapid clearance of the secondary infection were not affected by treatment with FTY720 before rechallenge. Moreover, adoptive transfer of lung CD4 TRM cells conferred protection in naive mice. Our findings reveal that Ag-specific CD4 TRM cells play a critical role in adaptive immunity against reinfection and memory induced by natural infection with B. pertussis.
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Inmunidad Adaptativa , Bordetella pertussis/inmunología , Linfocitos T CD4-Positivos/inmunología , Inmunidad Innata , Memoria Inmunológica , Pulmón/inmunología , Traslado Adoptivo , Animales , Linfocitos B/inmunología , Proliferación Celular , Clorhidrato de Fingolimod/administración & dosificación , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-17/inmunología , Interleucina-17/metabolismo , Pulmón/microbiología , Pulmón/patología , RatonesRESUMEN
One factor that impacts on microglial activation is the interaction between the ubiquitously expressed CD200 and CD200R, which is expressed only on microglia in the brain. Decreased signalling through CD200R, when CD200 expression is reduced, results in microglial activation and may, at least in part, explain the increased cell activity that is observed with age, in models of Alzheimer's and Parkinson's disease as well as in the human diseases. There is evidence of increased microglial activation in CD200-deficient mice, and isolated microglia prepared from these mice are more reactive to inflammatory stimuli like Toll-like receptor 2 and 4 agonists, and interferon-γ. Here, we examined the impact of CD200 deficiency on amyloid-ß (Aß)-induced changes in microglia and report, perhaps unexpectedly, that the effect of Aß was attenuated in microglia prepared from CD200-deficient mice. The evidence indicates that this is a consequence of increased phagocytosis, associated with increased lysosomal activity in CD200-deficient microglia. The data suggest that mTOR-related signalling is decreased in these cells and that inhibiting mTOR by rapamycin increases phagocytosis. Thus, while the findings to date have emphasized the anti-inflammatory effects of CD200-CD200R interaction, the present evidence indicates a previously unreported impact on lysosomal function.
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Antígenos CD/metabolismo , Lisosomas/metabolismo , Microglía/metabolismo , Fagocitosis/fisiología , Péptidos beta-Amiloides/metabolismo , Animales , Hipocampo/metabolismo , Interferón gamma/metabolismo , Activación de Macrófagos/fisiología , Masculino , Microglía/efectos de los fármacos , Ratas Wistar , Receptor Toll-Like 2/metabolismoRESUMEN
Ageing is a complex multifactorial process that results in many changes in physiological changes processes that ultimately increase susceptibility to a wide range of diseases. As such an ageing population is resulting in a pressing need for more and improved treatments across an assortment of diseases. Such treatments can come from a better understanding of the pathogenic pathways which, in turn, can be derived from models of disease. Therefore the more closely the model resembles the disease situation the more likely relevant the data will be that is generated from them. Here we review the state of knowledge of mouse models of a range of diseases and aspects of an ageing physiology that are all germane to ageing. We also give recommendations on the most common mouse models on their relevance to the clinical situations occurring in aged patients and look forward as to how research in ageing models can be carried out. As we continue to elucidate the pathophysiology of disease, often through mouse models, we also learn what is needed to refine these models. Such factors can include better models, reflecting the ageing patient population, or a better phenotypic understanding of existing models.
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Envejecimiento/metabolismo , Envejecimiento/patología , Modelos Animales de Enfermedad , Animales , Humanos , RatonesRESUMEN
The effects of Toll-like receptor (TLR) activation in peripheral cells are well characterized but, although several TLRs are expressed on cells of the brain, the consequences of their activation on neuronal function remain to be fully investigated, particularly in the context of assessing their potential as therapeutic targets in neurodegenerative diseases. Several endogenous TLR ligands have been identified, many of which are soluble factors released from cells exposed to stressors. In addition, amyloid-ß (Aß) the main constituent of the amyloid plaques in Alzheimer's disease (AD), activates TLR2, although it has also been shown to bind to several other receptors. The objective of this study was to determine whether activation of TLR2 played a role in the developing inflammatory changes and Aß accumulation in a mouse model of AD. Wild type and transgenic mice that overexpress amyloid precursor protein and presenilin 1 (APP/PS1 mice) were treated with anti-TLR2 antibody for 7months from the age of 7-14months. We demonstrate that microglial and astroglial activation, as assessed by MHCII, CD68 and GFAP immunoreactivity was decreased in anti-TLR2 antibody-treated compared with control (IgG)-treated mice. This was associated with reduced Aß plaque burden and improved performance in spatial learning. The data suggest that continued TLR2 activation contributes to the developing neuroinflammation and pathology and may be provide a strategy for limiting the progression of AD.