Endotoxin Augments Myeloid Dendritic Cell Influx into the Airways in Patients with Allergic Asthma

Abstract

Rationale: Epidemiologic studies have shown that exacerbation of asthma is modulated by environmental endotoxin. High levels of endotoxin are associated with asthma symptoms and the current use of asthma medication. However, the underlying mechanisms by which endotoxin modulates asthma are not completely understood. Objectives: The aim of the study was to test whether endotoxin enhances the response of individuals with allergic asthma to allergen, and to determine if this interaction is associated with increased numbers of antigen-presenting cells in the airways. Methods: Seventeen subjects with mild allergic asthma underwent segmental challenge with allergen, endotoxin, and the combination of both in three different lung segments via bronchoscopy. The cellular influx including monocytes, myeloid dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs), as well as the level of cytokines, were assessed in bronchoalveolar lavage fluid obtained 24 hours after segmental challenge. Monocytes, mDCs, and pDCs were isolated and their capacity to induce T cell proliferation was determined. Measurements and Main Results: Endotoxin enhanced the cellular response to allergen. The combination of allergen and endotoxin resulted in increased numbers of total cells, lymphocytes, neutrophils, eosinophils, monocytes, and mDCs, as well as increased levels of lipopolysaccharide-binding protein, IL-1a, IL-6, and tumor necrosis factor-a in the bronchoalveolar lavage fluid compared with allergen alone. Isolated mDCs but not pDCs induced a strong T cell proliferation in vitro. Conclusions: Endotoxin augments the allergic inflammation in the lungs of individuals with asthma, and induces an enhanced influx of monocytes and functionally active antigen-presenting mDCs into the respiratory tract.

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 a murine asthma model, myeloid dendritic cells (mDCs) accumulate in the allergen-challenged airways during the acute phase, and the depletion of mDCs attenuates the airway inflammation and hyperresponsiveness (10). 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).…”

Pathogenesis of Steroid-Resistant Airway Hyperresponsiveness: Interaction between IFN-γ and TLR4/MyD88 Pathways

“…Like neutrophils, lung macrophages are crucial in host defense against infections and have long been recognized as undergoing activation in asthma (29). Recently, Schaumann et al (30) have shown that LPS increases influx of macrophage-like cells into alveolar space and enhances allergic inflammation in the lung of asthmatics. Indeed, macrophage activation is tightly regulated by TLRs and IFN-␥, and these molecules have been shown to increase the production of proinflammatory cytokines (e.g., macrophage inflammatory protein 1␣, GM-CSF, and IL-12) and to activate transcriptional programs (e.g., NF-B and ERK1/2 MAPK) (31) in these cells.…”

House Dust Mite Allergens and the Induction of Monocyte Interleukin 1β Production That Triggers an IκBζ-Dependent Granulocyte Macrophage Colony-Stimulating Factor Release from Human Lung Epithelial Cells

“…Infiltration of mononuclear phagocytes into asthmatic airways is well documented (16,17), as is strong evidence for cross-talk between these cells and epithelial cells in asthma (15,31). Therefore, we first evaluated the role of mononuclear phagocytes in responding to HDM in our system.…”

“…There is also evidence of cross-talk between epithelial cells and dendritic cells that enhances the allergic response in asthma (15). Exposure to allergic antigens is associated with increased influx of monocytes, which differentiate into macrophages and dendritic cells in the airway mucosa of both mice and humans (16)(17)(18). Thus, understanding the molecular mechanisms that regulate the innate immune response involved in house dust mite-induced asthma is fundamental to the development of new therapeutics.…”