Impaired GATA3-Dependent Chromatin Remodeling and Th2 Cell Differentiation Leading to Attenuated Allergic Airway Inflammation in Aging Mice

Hasegawa, Akira; Miki, Takako; Hosokawa, Hiroyuki; Hossain, Mohammad B.; Shimizu, Chiaki; Hashimoto, Kimio; Kimura, Motoko; Yamashita, Masakatsu; Nakayama, Toshinori

doi:10.4049/jimmunol.176.4.2546

Cited by 22 publications

(23 citation statements)

References 56 publications

(62 reference statements)

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“…However, the effects of the aging process on inflammation associated with asthma have not been clarified. Some previous studies have reported that older antigen-sensitized and -challenged animals have a lower total cell count and eosinophils percentage in BAL fluid, and suppressed Th2 cytokines compared with young mice 2–4. However, recent data has shown that older OVA mice display greater inflammation compared with young 6-week-old mice 5,21.…”

Section: Discussionmentioning

confidence: 95%

Effect of aging on airway remodeling and muscarinic receptors in a murine acute asthma model

Kang¹,

Lee²,

Rhee³

et al. 2013

CIA

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Background and objectivesThe influence of aging on the development of asthma has not been studied thoroughly. The aim of this study was to investigate age-related airway responses involving lung histology and expression of muscarinic receptors in a murine model of acute asthma.MethodsFemale BALB/c mice at the ages of 6 weeks and 6, 9, and 12 months were sensitized and challenged with ovalbumin (OVA) for 1 month (n = 8–12 per group). We analyzed inflammatory cells and T-helper (Th)2 cytokines in bronchoalveolar lavage (BAL) fluid and parameters of airway remodeling and expression of muscarinic receptors in lung tissue.ResultsAmong the OVA groups, total cell and eosinophil numbers in BAL fluid were significantly higher in the older (6-, 9-, and 12-month-old) mice than in the young (6-week-old) mice. Interleukin (IL) 4 (IL-4) concentration increased, but IL-5 and IL-13 concentrations showed a decreased tendency, with age. IL-17 concentration tended to increase with age, which did not reach statistical significance. Periodic acid-Schiff (PAS) staining area, peribronchial collagen deposition, and area of α-smooth muscle staining were significantly higher in the 6-month older OVA group than in the young OVA group. The expression of the M3 and M2 muscarinic receptors tended to increase and decrease, respectively, with age.ConclusionThe aged mice showed an active and unique pattern not only on airway inflammation, but also on airway remodeling and expression of the muscarinic receptors during the development of acute asthma compared with the young mice. These findings suggest that the aging process affects the pathogenesis of acute asthma and age-specific approach might be more appropriate for better asthma control in a clinical practice.

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Section: Discussionmentioning

confidence: 95%

Effect of aging on airway remodeling and muscarinic receptors in a murine acute asthma model

Kang¹,

Lee²,

Rhee³

et al. 2013

CIA

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“…To date, the precise mechanisms of the development of respiratory tolerance in mice repeatedly challenged with OVA aerosols have not been elucidated, and both regulatory T cell-dependent [36] and regulatory T cell-independent [37] mechanisms have been proposed. One factor that may be important in the down-regulation of allergic airway inflammation and AHR over time could be the aging of mice, because some studies found that the capability of T cells to differentiate into Th-2 cells was reduced in aging mice [38, 39]. In contrast, one recent study found that older mice developed increased allergic inflammation, but less pronounced AHR [40].…”

Section: Discussionmentioning

confidence: 99%

Comparison of Acute Inflammatory and Chronic Structural Asthma-Like Responses between C57BL/6 and BALB/c Mice

Hove

Maes

Cataldo

et al. 2009

Int Arch Allergy Immunol

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Background: The interactions between airway responsiveness, structural remodelling and inflammation in allergic asthma remain poorly understood. Prolonged challenge with inhaled allergen is necessary to replicate many of the features of airway wall remodelling in mice. In both mice and humans, genetic differences can have a profound influence on allergy, inflammation, airway responsiveness and structural changes. Methods: The aim of this study was to provide a comparative analysis of allergen-induced airway changes in sensitized BALB/c and C57BL/6 mice that were exposed to inhaled allergen for 2 (‘acute’), 6 or 9 weeks (‘chronic’). Inflammation, remodelling and responsiveness were analyzed. Results: Both strains developed a Th-2-driven airway inflammation with allergen-specific IgE, airway eosinophilia and goblet cell hyperplasia upon 2 weeks of allergen inhalation. This was accompanied by a significant increase in airway smooth muscle mass and hyperresponsiveness in BALB/c but not in C57BL/6 mice. However, airway eosinophilia was more pronounced in the C57BL/6 strain. Chronic allergen exposure (6 or 9 weeks) resulted in an increase in airway smooth muscle mass as well as subepithelial collagen and fibronectin deposition in both strains. The emergence of these structural changes paralleled the disappearance of inflammation in both C57BL/6 and BALB/c mice and loss of hyperresponsiveness in the BALB/c strain. TGF-β₁was accordingly elevated in both strains. Conclusion: Airway inflammation, remodelling and hyperresponsiveness are closely intertwined processes. Genetic background influences several aspects of the acute allergic phenotype. Chronic allergen exposure induces a marked airway remodelling that parallels a decreased inflammation, which was largely comparable between the two strains.

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“…CD4 + T cells isolated from lamina propria were labeled with CFSE (Invitrogen) as described previously [52]. The cells were cultured in complete medium in the presence of Con A (2 µg/ml) (WAKO, Osaka, Japan) for 48 h, and then were analyzed on a FACSCalibur instrument (BD Biosciences).…”

Section: Methodsmentioning

confidence: 99%

Crucial Role for CD69 in the Pathogenesis of Dextran Sulphate Sodium-Induced Colitis

et al. 2013

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CD69 is a membrane molecule transiently expressed on activated lymphocytes, and its selective expression in inflammatory infiltrates suggests that it plays a role in the pathogenesis of inflammatory diseases. In this study, we used CD69-deficient (CD69 KO) mice to assess the role of CD69 in the pathogenesis of dextran sulphate sodium (DSS)-induced acute and chronic colitis. The severity of colitis was assessed by the survival rate, clinical signs, colon length, histological examination and the expression of cytokines and chemokines in the large intestines. Both acute and chronic colitis were attenuated in the CD69 KO mice, as reflected by the lower lethality, weight loss, clinical signs, and improved histological findings. CD69+ cells infiltrated extensively into the inflamed mucosa of the colon in WT mice after DSS treatment. Experiments with the transfer of WT CD4 T cells into CD69 KO mice restored the induction of colitis. The administration of an anti-CD69 antibody also inhibited the induction of the DSS-induced colitis. These results indicate that CD69 expressed on CD4 T cells plays an important role in the pathogenesis of DSS-induced acute and chronic colitis, and that CD69 could be a possible therapeutic target for colitis.

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Impaired GATA3-Dependent Chromatin Remodeling and Th2 Cell Differentiation Leading to Attenuated Allergic Airway Inflammation in Aging Mice

Cited by 22 publications

References 56 publications

Effect of aging on airway remodeling and muscarinic receptors in a murine acute asthma model

Effect of aging on airway remodeling and muscarinic receptors in a murine acute asthma model

Comparison of Acute Inflammatory and Chronic Structural Asthma-Like Responses between C57BL/6 and BALB/c Mice

Crucial Role for CD69 in the Pathogenesis of Dextran Sulphate Sodium-Induced Colitis

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