Importance of Myeloid Dendritic Cells in Persistent Airway Disease after Repeated Allergen Exposure

Abstract

Rationale: There is conflicting information about the development and resolution of airway inflammation and airway hyperresponsiveness (AHR) after repeated airway exposure to allergen in sensitized mice. Methods: Sensitized BALB/c and C57BL/6 mice were exposed to repeated allergen challenge on 3, 7, or 11 occasions. Airway function in response to inhaled methacholine was monitored; bronchoalveolar lavage fluid inflammatory cells were counted; and goblet cell metaplasia, peribronchial fibrosis, and smooth muscle hypertrophy were quantitated on tissue sections. Bone marrow-derived dendritic cells were generated after differentiation of bone marrow cells in the presence of growth factors. Results: Sensitization to ovalbumin (OVA) in alum, followed by three airway exposures to OVA, induced lung eosinophilia, goblet cell metaplasia, mild peribronchial fibrosis, and peribronchial smooth muscle hypertrophy; increased levels of interleukin (IL)-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor, transforming growth factor-␤ 1 , eotaxin-1, RANTES (regulated on activation, normal T-cell expressed and secreted), and OVA-specific IgG1 and IgE; and resulted in AHR. After seven airway challenges, development of AHR was markedly decreased as was the production of IL-4, IL-5, and IL-13. Levels of IL-10 in both strains and the level of IL-12 in BALB/c mice increased. After 11 challenges, airway eosinophilia and peribronchial fibrosis further declined and the cytokine and chemokine profiles continued to change. At this time point, the number of myeloid dendritic cells and expression of CD80 and CD86 in lungs were decreased compared with three challenges. After 11 challenges, intratracheal instillation of bone marrowderived dendritic cells restored AHR and airway eosinophilia. Conclusions: These data suggest that repeated allergen exposure leads to progressive decreases in AHR and allergic inflammation, through decreases in myeloid dendritic cell numbers.

Effect of Prostaglandin I2 Analogs on Cytokine Expression in Human Myeloid Dendritic Cells via Epigenetic Regulation

“…The crucial task of mDCs is the continuous surveillance of antigen-exposed sites throughout the body and the initiation of primary T-cell responses including T-cell polarization into Th1 and Th2 cells by secreting cytokines and expressing costimulatory molecules after activation (17,29). DCs, particular in mDCs, have a specific and important role in pathogenesis of human asthma (11)(12)(13). Recently, PGI 2 is regarded as a potential treatment of asthma by their antiinflammatory effect in vitro (14,30) and in animal model (15).…”

“…In human asthma, mDCs accumulate in bronchoalveolar lavage fluid after an allergen challenge (11), and the influx of mDCs into the airways can be augmented by endotoxins (12). The induction and maintenance of inflammatory responses to allergens in persistent airway disease needs the involvement of mDCs (13). These data suggested the critical role of mDCs in allergic airway inflammation.…”

Losartan inhibits conventional dendritic cell maturation and Th1 and Th17 polarization responses: Νovel mechanisms of preventive effects on lipopolysaccharide-induced acute lung injury

“…Isolation of left lung cells were performed as described in detail previously (21). Briefly, lungs were lavaged and dissected into small pieces finely using scissors, and then digested with type V collagenase.…”

Leukotriene B4 Receptor 1 Expression on Dendritic Cells Is Required for the Development of Th2 Responses and Allergen-Induced Airway Hyperresponsiveness

“…DCs were generated from bone marrow cells of naive BLT1 ϩ/ϩ or BLT1 Ϫ/Ϫ mice according to the procedure previously described (27). In brief, bone marrow cells obtained from femurs and tibias of mice were placed in culture medium with recombinant mouse GM-CSF (10 ng/ml) and recombinant mouse IL-4 (10 ng/ml; R&D Systems).…”

“…Under anesthesia, 1 ϫ 10 6 OVA-pulsed BMDCs in 40 l of PBS were instilled into naive BLT1 ϩ/ϩ mice through the trachea, under fiberoptic illumination (27). Control groups of mice received OVA-non-pulsed BMDCs.…”