Airway Epithelial Cells Regulate the Functional Phenotype of Locally Differentiating Dendritic Cells: Implications for the Pathogenesis of Infectious and Allergic Airway Disease

Abstract

Atopic asthma pathogenesis is driven by the combined effects of airway inflammation generated during responses to viral infections and aeroallergens, and both these pathways are regulated by dendritic cells (DC) that differentiate locally from monocytic precursors. These DCs normally exhibit a sentinel phenotype characterized by active Ag sampling but attenuated presentation capability, which limits the intensity of local expression of adaptive immunity. How this tight control of airway DC functions is normally maintained, and why it breaks down in some atopics leading to immunopathological changes in airway tissues, is unknown. We postulated that signals from adjacent airway epithelial cells (AEC) contribute to regulation of local differentiation of DC. We tested this in a coculture model containing both cell types in a GM-CSF-IL-4-enriched cytokine milieu characteristic of the atopic asthmatic airway mucosa. We demonstrate that contact with AEC during DC differentiation up-regulates expression of the function-associated markers MHC class II, CD40, CD80, TLR3, and TLR4 on DCs with concomitant up-regulation of Ag uptake/processing. Moreover, the AEC-conditioned DCs displayed increased LPS responsiveness evidenced by higher production of IL-12, IL-6, IL-10, and TNF-α. The Th2 memory-activating properties of AEC-conditioned DCs were also selectively attenuated. Data from microarray and blocking experiments implicate AEC-derived type 1 IFNs and IL-6 in modulation of DC differentiation. Collectively, these findings suggest that resting AECs modulate local DC differentiation to optimize antimicrobial defenses in the airways and in the process down-modulate capacity for expression of potentially damaging Th2 immunity.

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

“…However, dendritic cells have been reported to be the predominant innate immune cells lining the lung epithelium that respond to antigens (14,18,38). Notably, pulmonary dendritic cells described in these studies are naive, not mature, and are more like the monocytes used in our model.…”

“…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.…”

The Tobacco Smoke Component, Acrolein, Suppresses Innate Macrophage Responses by Direct Alkylation of c-Jun N-Terminal Kinase

“…Transcriptional profiling of AMs in smokers has indicated a marked macrophage reprogramming in smokers (3,4), with suppression of inflammatory genes associated with classical M1-related inflammatory/immune genes and induction of genes associated with various M2-polarization programs relevant to tissue remodeling and immunoregulation, findings that are consistent with reduced innate immune responses and increased susceptibility to respiratory infections in smokers or CS-exposed individuals (2,5). Actions of CS on airway epithelial cells affect their production of inflammatory or host defense mediators (6)(7)(8)(9) and their interactions with DCs (10,11). Furthermore, direct actions of CS on DCs may affect DC maturation (12) and polarize T helper (Th) 2 immune responses (13,14).…”

Interleukin-1α: a key player for epithelial-to-mesenchymal signalling in COPD?

“…Respiratory syncytial virus-infected BECs regulate CD8 + T-cell activation and antiviral activity, according to changes in epithelial expression of the "checkpoint" immune receptor PD-L1 [7]. BECs also regulate dendritic cell differentiation and maturation as well as responsiveness to lipopolysaccharide [8], and inhibit T-cell recall responses towards common aeroallergens in order to ensure mucosal homeostasis and dampen allergic responses [9]. It has also been shown in asthma that BECs may suppress constitutive and IgE-dependent histamine release by lung mast cells [10], further highlighting the central role of the epithelium in sensing and shaping mucosal danger signalling.…”