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2.
J Agric Food Chem ; 68(10): 3099-3111, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32067456

RESUMO

Sesamol, a lignan in sesame, possesses several bioactivities, such as antioxidation, anti-inflammation, and neuroprotective capability. In this study, the effects of sesamol on aging-caused cognitive defects are investigated. Twelve-month-old mice were treated with sesamol (0.1%, w/w) as dietary supplementation for 12 weeks. Behavioral tests revealed that sesamol improved aging-associated cognitive impairments. Sesamol decreased aging-induced oxidative stress via suppression of malondialdehyde production and increased antioxidant enzymes. Histological staining showed that sesamol treatment improved aging-induced neuronal damage and synaptic dysfunction in the hippocampus. Furthermore, sesamol significantly reduced aging-induced neuroinflammation by inhibiting the microglial overactivation and inflammatory cytokine expressions. Meanwhile, the accumulation of Aß1-42 was reduced by sesamol treatment. Moreover, sesamol protected the gut barrier integrity and reduced LPS release, which was highly associated with its beneficial effects on behavioral and inflammatory changes. In conclusion, our findings indicated that the use of sesamol is feasible in the treatment of aging-related diseases.


Assuntos
Envelhecimento/efeitos dos fármacos , Benzodioxóis/administração & dosagem , Disfunção Cognitiva/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Fenóis/administração & dosagem , Envelhecimento/imunologia , Envelhecimento/psicologia , Peptídeos beta-Amiloides/imunologia , Animais , Disfunção Cognitiva/imunologia , Disfunção Cognitiva/psicologia , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Humanos , Masculino , Malondialdeído/imunologia , Camundongos , Microglia/efeitos dos fármacos , Microglia/imunologia , Estresse Oxidativo/efeitos dos fármacos
3.
Adv Exp Med Biol ; 1216: 55-64, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31894547

RESUMO

Chronic inflammation, which is called "inflamm-aging" , is characterized by an increased level of inflammatory cytokines in response to physiological and environmental stressors, and causes the immune system to function consistently at a low level, even though it is not effective. Possible causes of inflammaging include genetic susceptibility, visceral obesity, changes in gut microbiota and permeability, chronic infections and cellular senescence. Inflammation has a role in the development of many age-related diseases, such as frailty. Low grade chronic inflammation can also increase the risk of atherosclerosis and insulin resistance which are the leading mechanisms in the development of cardiovascular diseases (CVD). As it is well known that the risk of CVD is higher in older people with frailty and the risk of frailty is higher in patients with CVD, there may be relationship between inflammation and the development of CVD and frailty. Therefore, this important issue will be discussed in this chapter.


Assuntos
Doenças Cardiovasculares/complicações , Idoso Fragilizado , Fragilidade/complicações , Inflamação/complicações , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/imunologia , Envelhecimento/patologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/patologia , Senescência Celular , Citocinas/imunologia , Fragilidade/imunologia , Fragilidade/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia
4.
Immunology ; 159(1): 39-51, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31777064

RESUMO

Immunity is shaped by commensal microbiota. From early life onwards, microbes colonize mucosal surfaces of the body and thereby trigger the establishment of immune homeostasis and defense mechanisms. Recent evidence reveals that the family of innate lymphoid cells (ILCs), which are mainly located in mucosal tissues, are essential in the maintenance of barrier functions as well as in the initiation of an appropriate immune response upon pathogenic infection. In this review, we summarize recent insights on the functional interaction of microbiota and ILCs at steady-state and throughout life. Furthermore, we will discuss the interplay of ILCs and the microbiota in mucosal infections focusing on intestinal immunity.


Assuntos
Bactérias/imunologia , Microbioma Gastrointestinal/imunologia , Imunidade Inata , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Linfócitos/imunologia , Linfócitos/microbiologia , Fatores Etários , Envelhecimento/imunologia , Animais , Bactérias/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Mucosa Intestinal/metabolismo , Linfócitos/metabolismo , Neoplasias/imunologia , Neoplasias/microbiologia , Transdução de Sinais
5.
Acta Clin Croat ; 58(Suppl 1): 29-34, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31741556

RESUMO

Among many functions of the body affected by the complex process of aging, the immune system, primarily due to declining of thymic function, the ancient and conserved evolutionary process, undergoes complex remodelling in the second part of life, with recapitulation of inversely evolutionary pattern of the immune system. In approaching the complex analysis of age-associated derangement of the immune system, homeostasis, and its clinical consequences, classical monoclonal lymphoproliferative syndrome (CLL) accompanied by a myriad of cellular and humoral defects, has been selected as appropriate and useful model for studies of impact T-cell and B-cell defects on appearance, evolution of clinical manifestations and outcome of CLL syndrome. Therefore imbalance in cascade secretion of a number of Th-1 (pro-inflammatory cytokines) and/or Th-2 (anti-inflammatory cytokines) in CLL patients with their pleiotropy, redundancy, synergistic and antagonistic activity and parallelism can cause variety of clinical manifestations as recurrent infections, systemic inflammation/sepsis, immunodeficiency, autoimmune disorder, indolent antiself malignancy, and/or other diverse secondary tumours.


Assuntos
Envelhecimento/imunologia , Sistema Imunitário/fisiopatologia , Leucemia Linfocítica Crônica de Células B/imunologia , Homeostase , Humanos , Conceitos Matemáticos , Biologia de Sistemas
6.
PLoS Biol ; 17(10): e3000383, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31661488

RESUMO

Thymic involution and proliferation of naive T cells both contribute to shaping the naive T-cell repertoire as humans age, but a clear understanding of the roles of each throughout a human life span has been difficult to determine. By measuring nuclear bomb test-derived 14C in genomic DNA, we determined the turnover rates of CD4+ and CD8+ naive T-cell populations and defined their dynamics in healthy individuals ranging from 20 to 65 years of age. We demonstrate that naive T-cell generation decreases with age because of a combination of declining peripheral division and thymic production during adulthood. Concomitant decline in T-cell loss compensates for decreased generation rates. We investigated putative mechanisms underlying age-related changes in homeostatic regulation of CD4+ naive T-cell turnover, using mass cytometry to profile candidate signaling pathways involved in T-cell activation and proliferation relative to CD31 expression, a marker of thymic proximity for the CD4+ naive T-cell population. We show that basal nuclear factor κB (NF-κB) phosphorylation positively correlated with CD31 expression and thus is decreased in peripherally expanded naive T-cell clones. Functionally, we found that NF-κB signaling was essential for naive T-cell proliferation to the homeostatic growth factor interleukin (IL)-7, and reduced NF-κB phosphorylation in CD4+CD31- naive T cells is linked to reduced homeostatic proliferation potential. Our results reveal an age-related decline in naive T-cell turnover as a putative regulator of naive T-cell diversity and identify a molecular pathway that restricts proliferation of peripherally expanded naive T-cell clones that accumulate with age.


Assuntos
Envelhecimento/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem da Célula/imunologia , Homeostase/imunologia , Timo/imunologia , Adulto , Idoso , Envelhecimento/genética , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Linhagem da Célula/genética , Proliferação de Células , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Homeostase/genética , Humanos , Imunofenotipagem , Interleucina-7/genética , Interleucina-7/imunologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , NF-kappa B/genética , NF-kappa B/imunologia , Fosforilação , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/imunologia , Transdução de Sinais , Timo/citologia , Timo/crescimento & desenvolvimento
7.
Nat Rev Nephrol ; 15(10): 625-640, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31477915

RESUMO

Immunosenescence involves a series of ageing-induced alterations in the immune system and is characterized by two opposing hallmarks: defective immune responses and increased systemic inflammation. The immune system is modulated by intrinsic and extrinsic factors and undergoes profound changes in response to the ageing process. Immune responses are therefore highly age-dependent. Emerging data show that immunosenescence underlies common mechanisms responsible for several age-related diseases and is a plastic state that can be modified and accelerated by non-heritable environmental factors and pharmacological intervention. In the kidney, resident macrophages and fibroblasts are continuously exposed to components of the external environment, and the effects of cellular reprogramming induced by local immune responses, which accumulate with age, might have a role in the increased susceptibility to kidney disease among elderly individuals. Additionally, because chronic kidney disease, especially end-stage renal disease, is often accompanied by immunosenescence, which affects these patients independently of age, and many kidney diseases are strongly age-associated, treatment approaches that target immunosenescence might be particularly clinically relevant.


Assuntos
Envelhecimento/imunologia , Imunossenescência , Rim/imunologia , Animais , Humanos , Rim/crescimento & desenvolvimento
8.
Int J Mol Sci ; 20(16)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398943

RESUMO

The immune response is essential to protect organisms from infection and an altered self. An organism's overall metabolic status is now recognized as an important and long-overlooked mediator of immunity and has spurred new explorations of immune-related metabolic abnormalities. Peroxisomes are essential metabolic organelles with a central role in the synthesis and turnover of complex lipids and reactive species. Peroxisomes have recently been identified as pivotal regulators of immune functions and inflammation in the development and during infection, defining a new branch of immunometabolism. This review summarizes the current evidence that has helped to identify peroxisomes as central regulators of immunity and highlights the peroxisomal proteins and metabolites that have acquired relevance in human pathologies for their link to the development of inflammation, neuropathies, aging and cancer. This review then describes how peroxisomes govern immune signaling strategies such as phagocytosis and cytokine production and their relevance in fighting bacterial and viral infections. The mechanisms by which peroxisomes either control the activation of the immune response or trigger cellular metabolic changes that activate and resolve immune responses are also described.


Assuntos
Suscetibilidade a Doenças , Imunidade , Inflamação/etiologia , Inflamação/metabolismo , Peroxissomos/metabolismo , Envelhecimento/genética , Envelhecimento/imunologia , Envelhecimento/metabolismo , Animais , Biomarcadores , Metabolismo Energético , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade/genética , Imunomodulação , Fagocitose/genética , Fagocitose/imunologia , Transdução de Sinais
9.
Curr Microbiol ; 76(11): 1278-1289, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31446476

RESUMO

The homeostatic systems, such as the nervous and immune systems, show deterioration in aging as a consequence of the age-related oxidative-inflammatory stress establishment. The supplementation with fermented milk containing probiotic bacteria could be a good nutritional strategy to improve homeostatic system functions in aged individuals through the modulation of their redox state. The aim of the present study was to evaluate the effect of 2-week supplementation with a commercial fermented milk containing yogurt species (Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus), and the probiotic Lactobacillus casei DN-114001 on behavior, redox state, and immune cell functions of aged mice as well as on their life span. Aged female ICR-CD1 mice were supplemented with fermented milk containing these probiotics for 2 weeks. After this period, a variety of behavioral tests were performed and several parameters of redox state and function of peritoneal leukocytes were analyzed. The results showed that the 2-week supplementation of fermented milk containing probiotics improved behavior (such as muscular vigor, exploratory activity, and anxiety-like behavior) as well as the redox state and functions of peritoneal immune cells in aged mice. In conclusion, the present study shows that the supplementation with fermented milk containing probiotics for a short period of time could be a good nutritional strategy to promote healthy aging.


Assuntos
Envelhecimento/imunologia , Envelhecimento/psicologia , Sistema Imunitário/efeitos dos fármacos , Probióticos/administração & dosagem , Iogurte/microbiologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Feminino , Humanos , Sistema Imunitário/imunologia , Lactobacillus casei/fisiologia , Lactobacillus delbrueckii/fisiologia , Camundongos , Camundongos Endogâmicos ICR , Oxirredução/efeitos dos fármacos , Streptococcus thermophilus/fisiologia , Iogurte/análise
10.
Int Arch Allergy Immunol ; 180(2): 150-158, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31284281

RESUMO

INTRODUCTION: Regulatory lymphocytes (CD4+ T regulatory cells [Treg], CD8+ Treg, and B regulatory cells [Breg]) play a critical role in immune homeostasis and tolerance. Common variable immunodeficiency (CVID) is associated with increased susceptibility to infections and increased frequency of inflammatory and autoimmune diseases. CD4+ Treg cell abnormalities have been reported in CVID; however, CD8+ Treg cells have not been reported in CVID. The objective of this study was to evaluate CD4+ Treg and CD8+ Treg cells in CVID patients. METHODS: In 25 patients with CVID and age-matched healthy controls, Treg cells, evaluated in freshly isolated peripheral blood mononuclear cells (natural; nCD4+ Treg and nCD8+ Treg) and following in vitro activation with anti-CD3/CD28 monoclonal antibodies (induced; iCD4+ Treg and iCD8+ Treg) as well as Breg cells were analyzed with specific monoclonal antibodies and isotype controls using flow cytometry. RESULTS: The proportions of nCD4+ Treg (CD4+ CD127low CD25high FoxP3+), iCD4+ Treg (CD4+ CD127low CD25high FoxP3+), iCD8+ Treg (CD8+ CD25high CD183+ FoxP3+), and Breg (CD19+ CD24high CD38high) lymphocytes were significantly lower in patients with CVID than in controls. CONCLUSIONS: Altered regulatory lymphocytes may play a role in the pathogenesis and autoimmunity and inflammation associated with CVID.


Assuntos
Linfócitos B Reguladores/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunodeficiência de Variável Comum/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Idoso , Envelhecimento/imunologia , Autoimunidade/imunologia , Feminino , Humanos , Inflamação/imunologia , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
Oxid Med Cell Longev ; 2019: 4574276, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281577

RESUMO

According to the oxidative-inflammatory theory of aging, there is a link between the function, the oxidative-inflammatory stress state of immune cells, and longevity. However, it is unknown which immune cell parameters can predict lifespan and if there would be any changes in this prediction, depending on the age of the subject. Therefore, a longitudinal study in mice was performed analysing immune function (chemotaxis of macrophages and lymphocytes, phagocytosis of macrophages, natural killer (NK) activity, and lymphoproliferation capacity), antioxidant (catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) activities as well as reduced glutathione (GSH) concentrations), oxidant (oxidized glutathione (GSSG), superoxide anion, and malondialdehyde (MDA) concentrations), and inflammation-related markers (basal release of IL-1ß, IL-6, TNF-α, and IL-10) in peritoneal leukocytes from mice at the adult, mature, old, very old, and long-lived ages (40, 56, 72, 96, and 120 ± 4 weeks of age, respectively). The results reveal that some of the investigated parameters are determinants of longevity at the adult age (lymphoproliferative capacity, lymphocyte chemotaxis, macrophage chemotaxis and phagocytosis, GPx activity, and GSH, MDA, IL-6, TNF-α, and IL-10 concentrations), and therefore, they could be proposed as markers of the rate of aging. However, other parameters are predictive of extreme longevity only at the very old age (NK activity, CAT and GR activities, and IL-6 and IL-1ß concentrations), and as such, they could reflect some of the adaptive mechanisms underlying the achievement of high longevity. Nevertheless, although preliminary, the results of the present study provide a new perspective on the use of function, redox, and inflammatory parameters in immune cells as prognostic tools in aging research and represent a novel benchmark for future work aimed at prediction of lifespan.


Assuntos
Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Inflamação/imunologia , Longevidade/imunologia , Estresse Oxidativo/imunologia , Envelhecimento/imunologia , Animais , Feminino , Células Matadoras Naturais/imunologia , Estudos Longitudinais , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos ICR , Oxirredução
12.
Hautarzt ; 70(8): 645-656, 2019 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-31270550

RESUMO

Herpes zoster (HZ) is caused by the reactivation of varicella zoster virus. The incidence of herpes zoster and associated problems increases with age. With a life-long prevalence of 30%, every second 85-year-old person experiences HZ once in his lifetime. Three therapeutic columns are based on antiviral, topical and analgetic therapies. An extreme handicap is acute and persistent pain which can develop into postherpetic neuralgia (PHN). Those pain symptoms are predominantly neuropathic. The management of acute and chronic manifestation of pain may be challenging. HZ vaccination represents a substantial improvement in terms of prevention of herpes zoster and reduction of long-term complications, such as PHN. The permanent vaccination commission of the Robert Koch Institute recommends vaccination with dead virus for all persons over the age of 60 years. Risk groups like immunosuppressed patients are advised to be vaccinated starting at the age of 50 years.


Assuntos
Vacina contra Herpes Zoster/administração & dosagem , Herpes Zoster/complicações , Herpesvirus Humano 3/patogenicidade , Neuralgia Pós-Herpética/prevenção & controle , Vacinação , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/imunologia , Antivirais/uso terapêutico , Herpes Zoster/tratamento farmacológico , Vacina contra Herpes Zoster/imunologia , Humanos , Pessoa de Meia-Idade , Neuralgia Pós-Herpética/tratamento farmacológico
14.
Nat Commun ; 10(1): 3042, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31316054

RESUMO

Stress resistance and longevity are positively correlated but emerging evidence indicates that they are physiologically distinct. Identifying factors with distinctive roles in these processes is challenging because pro-longevity genes often enhance stress resistance. We demonstrate that TCER-1, the Caenorhabditis elegans homolog of human transcription elongation and splicing factor, TCERG1, has opposite effects on lifespan and stress resistance. We previously showed that tcer-1 promotes longevity in germline-less C. elegans and reproductive fitness in wild-type animals. Surprisingly, tcer-1 mutants exhibit exceptional resistance against multiple stressors, including infection by human opportunistic pathogens, whereas, TCER-1 overexpression confers immuno-susceptibility. TCER-1 inhibits immunity only during fertile stages of life. Elevating its levels ameliorates the fertility loss caused by infection, suggesting that TCER-1 represses immunity to augment fecundity. TCER-1 acts through repression of PMK-1 as well as PMK-1-independent factors critical for innate immunity. Our data establish key roles for TCER-1 in coordinating immunity, longevity and fertility, and reveal mechanisms that distinguish length of life from functional aspects of aging.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Regulação da Expressão Gênica/fisiologia , Imunidade Inata/genética , Longevidade/genética , Fatores de Alongamento de Peptídeos/metabolismo , Estresse Fisiológico/imunologia , Envelhecimento/genética , Envelhecimento/imunologia , Animais , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/imunologia , Suscetibilidade a Doenças/imunologia , Fertilidade/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Modelos Animais , Mutação , Fatores de Alongamento de Peptídeos/genética , Fatores de Alongamento de Peptídeos/imunologia , Estresse Fisiológico/genética
15.
Hum Immunol ; 80(9): 703-713, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31331679

RESUMO

The 'Immunogenetics of Aging' project is a component introduced in the 14th International HLA and Immunogenetics Workshop (IHIW) and developed further within subsequent workshops. The aim was to determine the relevance of immunogenetic markers, focusing on HLA, cytokine genes, and some innate immunity genes, for successful aging and an increased capacity to reach the extreme limits of life-span. Within the 17th IHIW we applied Next Generation Sequencing methods to refine further HLA associations at allele level in longevity, and to extend our knowledge to additional loci such as HLA-DQA1, HLA-DPB1 and HLA-DPA1. Analysis of relatively small number of healthy elderly and young controls from four populations showed that some HLA class I and class II alleles were significantly positively associated with healthy aging. Additionally we observed statistically significant differences in HLA allele distribution when the analysis was performed separately in elderly females and males compared to sex-matched young controls. Haplotypes, probably associated with better control of viral and malignant diseases were increased in the elderly sample. These preliminary NGS data could confirm our hypotheses that survival and longevity might be associated with selection of HLA alleles and haplotypes conferring disease resistance or susceptibility. Therefore HLA alleles and haplotypes could be informative immunogenetic markers for successful ageing.


Assuntos
Envelhecimento/genética , Envelhecimento/imunologia , Educação , Sequenciamento de Nucleotídeos em Larga Escala , Imunogenética/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Biomarcadores , Feminino , Frequência do Gene/genética , Loci Gênicos , Antígenos HLA/genética , Haplótipos/genética , Humanos , Masculino , Polimorfismo Genético , População/genética , Adulto Jovem
16.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340438

RESUMO

Cancer immunotherapy has entered the forefront of cancer treatment, but major challenges still exist, such as the limited proportion of patients that respond to treatment and treatment-related toxicity. Therefore, biomarkers to predict which patients will benefit from therapy without major side effects are of the utmost importance. Moreover, novel therapeutic targets to increase the proportion of responding patients on a given immunotherapy or to alleviate immunotherapy-induced toxicity could be a valuable adjunct to immunotherapy treatment. Host factors such as age, obesity, and the composition of the gut microbiome have considerable effects on immune responses and, hence, could have a large impact on the outcome of immunotherapies. Moreover, since these host factors differ considerably between preclinical mouse models and human cancer patients, it might be possible that these host factors account, in part, for the observed discrepancies in outcomes between mice experiments and clinical trials. In this review, we discuss the latest data on the influence of aging, obesity, and the gut microbiome on the anti-tumor immune response and immunotherapy and propose avenues to increase our knowledge on this topic in order to improve patient selection for cancer immunotherapy treatment.


Assuntos
Envelhecimento/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Microbioma Gastrointestinal/imunologia , Regulação Neoplásica da Expressão Gênica , Imunoterapia/métodos , Neoplasias/terapia , Obesidade/terapia , Envelhecimento/genética , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Biomarcadores Farmacológicos/análise , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Modelos Animais de Doenças , Humanos , Camundongos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/microbiologia , Obesidade/genética , Obesidade/imunologia , Obesidade/microbiologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais
17.
EMBO J ; 38(17): e101064, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31359456

RESUMO

Alzheimer's disease is the most prevalent type of dementia and is caused by the deposition of extracellular amyloid-beta and abnormal tau phosphorylation. Neuroinflammation has emerged as an additional pathological component. Microglia, representing the brain's major innate immune cells, play an important role during Alzheimer's. Once activated, microglia show changes in their morphology, characterized by a retraction of cell processes. Systemic inflammation is known to increase the risk for cognitive decline in human neurogenerative diseases including Alzheimer's. Here, we assess for the first time microglial changes upon a peripheral immune challenge in the context of aging and Alzheimer's in vivo, using 2-photon laser scanning microscopy. Microglia were monitored at 2 and 10 days post-challenge by lipopolysaccharide. Microglia exhibited a reduction in the number of branches and the area covered at 2 days, a phenomenon that resolved at 10 days. Systemic inflammation reduced microglial clearance of amyloid-beta in APP/PS1 mice. NLRP3 inflammasome knockout blocked many of the observed microglial changes upon lipopolysaccharide, including alterations in microglial morphology and amyloid pathology. NLRP3 inhibition may thus represent a novel therapeutic target that may protect the brain from toxic peripheral inflammation during systemic infection.


Assuntos
Envelhecimento/imunologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Inflamação/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Envelhecimento/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/imunologia , Animais , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Humanos , Inflamação/induzido quimicamente , Inflamação/diagnóstico por imagem , Lipopolissacarídeos/efeitos adversos , Camundongos , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/metabolismo , Microscopia Confocal , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética
18.
Nat Commun ; 10(1): 2443, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164642

RESUMO

Ageing is a complex multifactorial process associated with a plethora of disorders, which contribute significantly to morbidity worldwide. One of the organs significantly affected by age is the gut. Age-dependent changes of the gut-associated microbiome have been linked to increased frailty and systemic inflammation. This change in microbial composition with age occurs in parallel with a decline in function of the gut immune system; however, it is not clear whether there is a causal link between the two. Here we report that the defective germinal centre reaction in Peyer's patches of aged mice can be rescued by faecal transfers from younger adults into aged mice and by immunisations with cholera toxin, without affecting germinal centre reactions in peripheral lymph nodes. This demonstrates that the poor germinal centre reaction in aged animals is not irreversible, and that it is possible to improve this response in older individuals by providing appropriate stimuli.


Assuntos
Envelhecimento/imunologia , Disbiose/imunologia , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/imunologia , Centro Germinativo/imunologia , Nódulos Linfáticos Agregados/imunologia , Animais , Toxina da Cólera/imunologia , Feminino , Imunização , Imunoglobulina A/imunologia , Camundongos , Nitrofenóis/imunologia , Fenilacetatos/imunologia
19.
Nat Commun ; 10(1): 2387, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160572

RESUMO

Senescent cells accumulate in human tissues during ageing and contribute to age-related pathologies. The mechanisms responsible for their accumulation are unclear. Here we show that senescent dermal fibroblasts express the non-classical MHC molecule HLA-E, which interacts with the inhibitory receptor NKG2A expressed by NK and highly differentiated CD8+ T cells to inhibit immune responses against senescent cells. HLA-E expression is induced by senescence-associated secretary phenotype-related pro-inflammatory cytokines, and is regulated by p38 MAP kinase signalling in vitro. Consistently, HLA-E expression is increased on senescent cells in human skin sections from old individuals, when compared with those from young, and in human melanocytic nevi relative to normal skin. Lastly, blocking the interaction between HLA-E and NKG2A boosts immune responses against senescent cells in vitro. We thus propose that increased HLA-E expression contributes to persistence of senescent cells in tissues, thereby suggesting a new strategy for eliminating senescent cells during ageing.


Assuntos
Envelhecimento/imunologia , Linfócitos T CD8-Positivos/imunologia , Senescência Celular/imunologia , Fibroblastos/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Células Matadoras Naturais/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Adulto , Idoso , Envelhecimento/patologia , Citocinas/imunologia , Derme/citologia , Fibroblastos/patologia , Humanos , Técnicas In Vitro , Nevo Pigmentado/congênito , Nevo Pigmentado/imunologia , Nevo Pigmentado/patologia , Fenótipo , RNA Interferente Pequeno , Transdução de Sinais , Pele/imunologia , Pele/patologia , Adulto Jovem , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
20.
Exp Anim ; 68(4): 483-490, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31155554

RESUMO

IL-17-producing T helper cells (Th17) are attracting attention as a new CD4-positive subset of T cells, reported to be responsible for various autoimmune diseases through stimulation of the release of inflammatory cytokines from target cells. However, most investigations of Th17 mediation of autoimmune diseases have focused on the experimental autoimmune models derived from young animals, with few studies that have analyzed physiological factors such as aging. The present study analyzed autoreactive T cells established in a syngeneic mixed lymphocyte culture (sMLC) from aged mice and examined their similarity with Th17. IL-17-producing autoreactive CD4-intermediate T cells were observed in the sMLC; these expressed several stem cell markers or an immunosuppressive receptor PD-1 on the cell surface and so seemed to be different to typical Th17 cells. RT-PCR analysis revealed that purified Th17-like cells also expressed Il17a, Il17f, Il23r, Rorc and Tdt mRNA, but not Rag1 or Rag2 mRNA. These findings that it is likely that Th17-like cells are involved in autoimmune responses in aged mice.


Assuntos
Envelhecimento/imunologia , Doenças Autoimunes/imunologia , Autoimunidade , Linfócitos T CD4-Positivos/imunologia , Interleucina-17/biossíntese , Células Th17/imunologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C
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