AHR

Aryl hydrocarbon receptor precursor (Ah receptor) (AhR) (Class E basic helix-loop-helix protein 76) (bHLHe76) [BHLHE76]

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Indoles from the commensal microbiota act via the AHR and IL-10 to tune the cellular composition of the colonic epithelium during aging.

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Role of the Aryl Hydrocarbon Receptor in Environmentally Induced Skin Aging and Skin Carcinogenesis.

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Loss of Neurogenesis in Aging Hydra.

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Environmental cues received during development shape dendritic cell responses later in life.

PubMed

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Environmental signals mediated via the aryl hydrocarbon receptor (AHR) shape the developing immune system and influence immune function. Developmental exposure to AHR binding chemicals causes persistent changes in CD4 and CD8 T cell responses later in life, including dampened clonal expansion and differentiation during influenza A virus (IAV) infection. Naïve T cells require activation by dendritic cells (DCs), and AHR ligands modulate the function of DCs from adult organisms. Yet, the consequences of developmental AHR activation by exogenous ligands on DCs later in life has not been examined. We report here that early life activation of AHR durably reduces the ability of DC to activate naïve IAV-specific CD8 T cells; however, activation of naïve CD4 T cells was not impaired. Also, DCs from developmentally exposed offspring migrated more poorly than DCs from control dams in both in vivo and ex vivo assessments of DC migration. Conditional knockout mice, which lack Ahr in CD11c lineage cells, suggest that dampened DC emigration is intrinsic to DCs. Yet, levels of chemokine receptor 7 (CCR7), a key regulator of DC trafficking, were generally unaffected. Gene expression analyses reveal changes in Lrp1, Itgam, and Fcgr1 expression, and point to alterations in genes that regulate DC migration and antigen processing and presentation as being among pathways disrupted by inappropriate AHR signaling during development. These studies establish that AHR activation during development causes long-lasting changes to DCs, and provide new information regarding how early life environmental cues shape immune function later in life.

MeSH Terms

Aging
Animals
Bone Marrow Cells
CD11c Antigen
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Cell Differentiation
Cell Movement
Dendritic Cells
Female
Gene Expression Regulation, Developmental
Immune System
Influenza A Virus, H3N2 Subtype
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Polychlorinated Dibenzodioxins
Receptors, Aryl Hydrocarbon
Receptors, CCR7

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Nursing Home Use After Implantable Cardioverter-Defibrillator Implantation in Older Adults: Results from the National Cardiovascular Data Registry.

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Genetic variants associated with skin aging in the Chinese Han population.

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Smoking and Obesity Increase Airway Hyperesponsiveness Risk in the Elderly.

PubMed

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of our study was assessing whether smoking and obesity might affect airways hyperresponsiveness (AHR) differently in younger and older subjects and whether this influence might be due to their different impacts on baseline lung function values at different ages. 3,903 consecutive adult subjects with normal lung function (1,920 males; mean age 35.1±16.2; median FEV1:97.3% of predicted [interquartile range (IQR):89.7-105.2] and FEV1/FVC: 84.6% of predicted [IQR:79.8-89.2]), having performed a methacholine test, were considered. They were subdivided into three groups according to age (18-39, 40-64 and ≥ 65 years) and into different sub-groups according to body mass index (BMI) and smoking habits, considering two AHR level cut-offs (PD20≤ 1600 μg and PD20≤ 800 μg). PD20 was significantly lower (p<0.004) in obese subjects aged 18-39 years, in comparison to older patients. Smoking was an AHR risk factor for subjects aged 40-64 and especially for those aged >65 (OR: 12.786 [IQR: 1.450-112.753]; p<0.0001). Obesity caused an AHR risk only in older subjects (>65 years) (OR: 3.120 [IQR: 1.144-8.509]; p<0.0001). FEV1/FVC and FEF25-75% decreased progressively (p<0.001) with age in subjects with different weights/smoking habits. No reductions with age were observed in FEV1% and FVC% except for a significant FVC% decrease in older smokers compared to older non-smokers. Smoking determined a progressively increasing AHR risk reaching its peak in the elderly. In younger obese individuals, AHR was higher than in obese elderly, whereas obesity was a higher AHR risk factor only in subjects aged >65 years. A small airway age-related reduction may cause the increased smoking/obesity induced AHR risk in older people.

MeSH Terms

Adolescent
Adult
Aged
Aging
Bronchial Provocation Tests
Female
Forced Expiratory Volume
Humans
Male
Methacholine Chloride
Middle Aged
Obesity
Respiratory Hypersensitivity
Retrospective Studies
Risk Factors
Smoking
Vital Capacity
Young Adult

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Impaired glucose and lipid metabolism in ageing aryl hydrocarbon receptor deficient mice.

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Enhanced allergic airway disease in old mice is associated with a Th17 response.

PubMed

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The prevalence of asthma in the elderly is increasing and associated with higher mortality than in children or young adults. However, the effects of age on the development and character of allergic asthma have been understudied. It has been suggested that mixed Th2/Th17 responses cause more severe forms of asthma, but the role of Th17 response in allergic airway disease and aging is not well understood. To investigate age-dependent characteristics and Th17 immune response in allergic airway disease in a murine house dust mite (HDM)-allergen model. Twelve-week-old and 15-month-old male BALB/c mice were sensitized and challenged with HDM. Bronchoalveolar lavage fluid (BALF), airway inflammation and hyperresponsiveness (AHR), serum immunoglobulin and splenic T cells were assessed. Age-related T cell activation was analyzed in a co-culture with bone marrow-derived dendritic cells (BMDC) and splenic CD4( ) T cells from young and old mice. Features of allergic airway disease such as mucous cell hyperplasia, infiltration of airway eosinophils and lymphocytes, Th2 cytokine expression and serum IgG1 levels were greater in old compared to young mice. In contrast to the more marked inflammatory/immune responses to HDM in old mice, AHR was greater in young HDM-treated mice. Only the old mice developed airway neutrophil infiltration and a Th17 immune response upon HDM exposure, with increases in BALF cytokines IL-17A and KC, and Th17 cytokine producing T cells in the spleen. Stimulation of CD4( ) T cells and BMDC co-cultures with HDM, resulted in an enhanced Th17 cytokine response in cells isolated from old mice. Our findings in mice suggest that the severity and character of allergic airway disease are age dependent, with a bias towards a Th17 immune response with aging. Elderly, asthmatics may be prone to develop severe allergic airway inflammation with a mixed Th2/Th17 immune response.

MeSH Terms

Age Factors
Animals
Asthma
CD4-Positive T-Lymphocytes
Cytokines
Dendritic Cells
Immunoglobulin G
Male
Mice
Mice, Inbred BALB C
Pyroglyphidae
Th17 Cells
Th2 Cells

Keywords

Th17
aging
allergic asthma
house dust mite
mice

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Influenza A infection enhances antigen-induced airway inflammation and hyperresponsiveness in young but not aged mice.

PubMed

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Although morbidity and mortality rates from asthma are highest in patients > 65 years of age, the effect of older age on airway inflammation in asthma is not well established. To investigate age-related differences in the promotion of allergic inflammation after influenza A viral respiratory infection on antigen-specific IgE production, antigen-induced airway inflammation and airway hyperresponsiveness in mice. To accomplish this objective, the following model system was used. Young (6 week) and aged (18 months) BALB/c mice were first infected with a non-lethal dose of influenza virus A (H/HKx31). Mice were then ovalbumin (OVA)-sensitized during the acute infection (3-days post inoculation) and then chronically underwent challenge to the airways with OVA. Forty-eight hours after the final OVA challenge, airway hyperresponsiveness (AHR), bronchoalveolar fluid (BALF) cellular and cytokine profile, antigen-specific IgE and IgG1, and lung tissue inflammation were measured. Age-specific differences were noted on the effect of a viral infection, allergic sensitization, airway inflammation and airway hyperresponsiveness. Serum OVA-specific IgE was significantly increased in only the aged mice infected with influenza virus. Despite greater morbidity (e.g. weight loss and sickness scores) during the acute infection in the 18-month old mice that were OVA-sensitized, there was little effect on the AHR and BALF cellular differential. In contrast, BALF neutrophils and AHR increased, but eosinophils decreased in 6-week mice that were OVA-sensitized during an acute influenza infection. With increased age in a mouse model, viral infection prior to antigen sensitization affects the airway and systemic allergic response differently. These differences may reflect distinct phenotypic features of allergic inflammation in older patients with asthma.

MeSH Terms

Age Factors
Animals
Antigens
Asthma
Bronchoalveolar Lavage Fluid
Cytokines
Disease Models, Animal
Female
Immunoglobulin E
Influenza A virus
Leukocyte Count
Lung
Mice
Orthomyxoviridae Infections
Ovalbumin
Respiratory Hypersensitivity

Keywords

aging
asthma
influenza
murine model

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A novel kinase regulates dietary restriction-mediated longevity in Caenorhabditis elegans.

PubMed

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Although dietary restriction (DR) is known to extend lifespan across species, from yeast to mammals, the signalling events downstream of food/nutrient perception are not well understood. In Caenorhabditis elegans, DR is typically attained either by using the eat-2 mutants that have reduced pharyngeal pumping leading to lower food intake or by feeding diluted bacterial food to the worms. In this study, we show that knocking down a mammalian MEKK3-like kinase gene, mekk-3 in C. elegans, initiates a process similar to DR without compromising food intake. This DR-like state results in upregulation of beta-oxidation genes through the nuclear hormone receptor NHR-49, a HNF-4 homolog, resulting in depletion of stored fat. This metabolic shift leads to low levels of reactive oxygen species (ROS), potent oxidizing agents that damage macromolecules. Increased beta-oxidation, in turn, induces the phase I and II xenobiotic detoxification genes, through PHA-4/FOXA, NHR-8 and aryl hydrocarbon receptor AHR-1, possibly to purge lipophilic endotoxins generated during fatty acid catabolism. The coupling of a metabolic shift with endotoxin detoxification results in extreme longevity following mekk-3 knock-down. Thus, MEKK-3 may function as an important nutrient sensor and signalling component within the organism that controls metabolism. Knocking down mekk-3 may signal an imminent nutrient crisis that results in initiation of a DR-like state, even when food is plentiful.

MeSH Terms

Animals
Biotransformation
Caenorhabditis elegans
Caenorhabditis elegans Proteins
Caloric Restriction
Conserved Sequence
Electron Transport Complex II
Fatty Acids
Gene Knockdown Techniques
Inactivation, Metabolic
Insulin
Longevity
Muscles
Oligonucleotide Array Sequence Analysis
Oxidation-Reduction
Protein-Serine-Threonine Kinases
Reactive Oxygen Species
Signal Transduction
Subcutaneous Tissue
Transcription Factors
Transforming Growth Factor beta
Up-Regulation
Xenobiotics

Keywords

Caenorhabditis elegans
beta-oxidation
dietary restriction
fat storage
lifespan
xenobiotic detoxification

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Early postnatal, but not late, exposure to chemical ambient pollutant 1,2-naphthoquinone increases susceptibility to pulmonary allergic inflammation at adulthood.

PubMed

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High diesel exhaust particle levels are associated with increased health effects; however, knowledge on the impact of its chemical contaminant 1,2-naphthoquinone (1,2-NQ) is limited. We investigated whether postnatal and adult exposures to 1,2-NQ influence allergic reaction and the roles of innate and adaptive immunity. Male neonate (6 days) and adult (56 days) C57Bl/6 mice were exposed to 1,2-NQ (100 nM; 15 min) for 3 days, and on day 59, they were sensitized and later challenged with ovalbumin (OVA). Airway hyper-responsiveness (AHR) and production of cytokines, immunoglobulin E (IgE) and leukotriene B4 (LTB4) were measured in the airways. Postnatal exposure to 1,2-NQ activated dendritic cells in splenocytes by increasing expressing cell surface molecules (e.g., CD11c). Co-exposure to OVA effectively polarized T helper (Th) type 2 (Th2) by secreting Th2-mediated cytokines. Re-stimulation with unspecific stimuli (PMA and ionomycin) generated a mixed Th1 (CD4( )/IFN-γ( )) and Th17 (CD4( )/IL-17( )) phenotype in comparison with the vehicle-matched group. Postnatal exposure to 1,2-NQ did not induce eosinophilia in the airways at adulthood, although it evoked neutrophilia and exacerbated OVA-induced eosinophilia, Th2 cytokines, IgE and LTB4 production without affecting AHR and mast cell degranulation. At adulthood, 1,2-NQ exposure evoked neutrophilia and increased Th1/Th2 cytokine levels, but failed to affect OVA-induced eosinophilia. In conclusion, postnatal exposure to 1,2-NQ increases the susceptibility to antigen-induced asthma. The mechanism appears to be dependent on increased expression of co-stimulatory molecules, which leads to cell presentation amplification, Th2 polarization and enhanced LTB4, humoral response and Th1/Th2 cytokines. These findings may be useful for future investigations on treatments focused on pulmonary illnesses observed in children living in heavy polluted areas.

MeSH Terms

Adaptive Immunity
Aging
Air Pollutants
Animals
Animals, Newborn
Cytokines
Disease Susceptibility
Immunity, Innate
Immunoglobulin E
Inhalation Exposure
Leukotriene B4
Male
Naphthoquinones
Ovalbumin
Pneumonia
Respiratory Hypersensitivity
Vehicle Emissions

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Airway hyperresponsiveness is associated with airway remodeling but not inflammation in aging Cav1-/- mice.

PubMed

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Airway inflammation and airway remodeling are the key contributors to airway hyperresponsiveness (AHR), a characteristic feature of asthma. Both processes are regulated by Transforming Growth Factor (TGF)-β. Caveolin 1 (Cav1) is a membrane bound protein that binds to a variety of receptor and signaling proteins, including the TGF-β receptors. We hypothesized that caveolin-1 deficiency promotes structural alterations of the airways that develop with age will predispose to an increased response to allergen challenge. AHR was measured in Cav1-deficient and wild-type (WT) mice 1 to 12 months of age to examine the role of Cav1 in AHR and the relative contribution of inflammation and airway remodeling. AHR was then measured in Cav1-/- and WT mice after an ovalbumin-allergen challenge performed at either 2 months of age, when remodeling in Cav1-/- and WT mice was equivalent, and at 6 months of age, when the Cav1-/- mice had established airway remodeling. Cav1-/- mice developed increased thickness of the subepithelial layer and a correspondingly increased AHR as they aged. In addition, allergen-challenged Cav1-/- mice had an increase in AHR greater than WT mice that was largely independent of inflammation. Cav1-/- mice challenged at 6 months of age have decreased AHR compared to those challenged at 2 months with correspondingly decreased BAL IL-4 and IL-5 levels, inflammatory cell counts and percentage of eosinophils. In addition, in response to OVA challenge, the number of goblet cells and α-SMA positive cells in the airways were reduced with age in response to OVA challenge in contrast to an increased collagen deposition further enhanced in absence of Cav1. A lack of Cav1 contributed to the thickness of the subepithelial layer in mice as they aged resulting in an increase in AHR independent of inflammation, demonstrating the important contribution of airway structural changes to AHR. In addition, age in the Cav1-/- mice is a contributing factor to airway remodeling in the response to allergen challenge.

MeSH Terms

Actins
Aging
Airway Remodeling
Animals
Asthma
Bronchial Hyperreactivity
Caveolin 1
Collagen
Disease Models, Animal
Female
Interleukin-4
Interleukin-5
Mice
Mice, Inbred C57BL
Mice, Knockout
Ovalbumin
Pneumonia
Transforming Growth Factor beta

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Ventilation heterogeneity is associated with airway responsiveness in asthma but not COPD.

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Relationship between airway pathophysiology and airway inflammation in older asthmatics.

PubMed

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Asthma-related morbidity is greater in older compared with younger asthmatics. Airway closure is also greater in older asthmatics, an observation that may be explained by differences in airway inflammation. We hypothesized that in older adult patients with asthma, neutrophil airway inflammation increases airway closure during bronchoconstriction, while eosinophil airway inflammation increases airway hyperresponsiveness (AHR). Asthmatic subjects (n = 26), aged ≥55 years (68% female), were studied, and AHR to 4.5% saline challenge was measured by the response-dose ratio (�ll in forced expiratory volume in 1 s (FEV1 )/mg saline). Airway closure was assessed during bronchoconstriction percent change in forced vital capacity (FVC)/percent change in FEV1 (i.e. Closing Index). Airway inflammation was assessed by induced sputum and exhaled nitric oxide (eNO). Mean patient age was 67 years (confidence interval: 63-71) with a mean FEV1 of 78 % predicted (confidence interval: 70-85%). AHR correlated with sputum eosinophils (r = 0.68, P = 0.005) and eNO (r = 0.71, P < 0.001), but not with neutrophils or neutrophil mediators. The Closing Index correlated with total sputum neutrophils (r = 0.66, P = 0.005), neutrophil elastase, matrix metalloproteinase-9 and interleukin-8 (all P < 0.05). Further, FEV1 /FVC and residual volume/total lung capacity at rest correlated with neutrophil elastase (r = -0.46 and 0.66 respectively, P < 0.05) but not with eosinophils or eNO. In older patients with asthma, airway inflammatory cells are linked to abnormal airway physiology. Eosinophilic airway inflammation is associated with AHR while neutrophilic inflammation may be an important determinant of airflow limitation at rest and airway closure during bronchoconstriction. The clinical implications of these findings remain to be determined.

MeSH Terms

Age Factors
Aged
Aging
Asthma
Bronchoconstriction
Eosinophils
Female
Forced Expiratory Volume
Humans
Leukocyte Elastase
Male
Matrix Metalloproteinase 9
Middle Aged
Neutrophils
Nitric Oxide
Pneumonia
Respiratory Function Tests
Respiratory System

Keywords

airway closure
airway hyper responsiveness
airway inflammation
asthma
elderly

AHR

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