Airway Epithelial Cells Release MIP-3α/CCL20 in Response to Cytokines and Ambient Particulate Matter

Abstract

The initiation and maintenance of airway immune responses in Th2 type allergic diseases such as asthma are dependent on the specific activation of local airway dendritic cells (DCs). The cytokine microenvironment, produced by local cells, influences the recruitment of specific subsets of immature DCs and their subsequent maturation. In the airway, DCs reside in close proximity to airway epithelial cells (AECs). We examined the ability of primary culture human bronchial epithelial cells (HBECs) to synthesize and secrete the recently described CC-chemokine, MIP-3alpha/CCL20. MIP-3alpha/CCL20 is the unique chemokine ligand for CCR6, a receptor with a restricted distribution. MIP-3alpha/CCL20 induces selective migration of DCs because CCR6 is expressed on some immature DCs but not on CD14+ DC precursors or mature DCs. HBECs were stimulated with pro-inflammatory cytokines tumor necrosis factor-alpha and interleukin (IL)-1beta or, because of their critical role in allergic diseases, IL-4 and IL-13. Cells were also exposed to small size-fractions of ambient particulate matter. Each of these stimuli induced MIP-3alpha/CCL20 gene and protein expression. Moreover, these agents upregulated mitogen-activated protein kinase pathways in HBECs. Inhibition of the ERK1/2 pathway or p38 reduced cytokine-induced MIP-3alpha/CCL20 expression. These data suggest a mechanism by which AEC may facilitate recruitment of DC subsets to the airway.

Impact of Bronchial Epithelium on Dendritic Cell Migration and Function: Modulation by the Bacterial Motif KpOmpA

“…CCL20 expression, but not that of inflammation-related chemokines, determines LC homing in the epidermis (23), the tonsils and probably also in the lung (24). CCL20 secretion by BEC was previously reported after exposure to allergen, but only in allergic asthmatic patients and to diesel exhaust particles (11,12). Therefore, CCL20 secretion is only induced by strong signals in BEC such as pathogen exposure or by proinflammatory mediators present within the lung environment.…”

“…Recent data suggest that DC behavior is locally controlled by lung environment and particularly by bronchial epithelial cells (BEC) (9 -11). In addition to GM-CSF, these BEC produce several cytokines and chemokines and express adhesion molecules potentially involved in DC traffic, as shown after exposure to diesel exhausted particles or allergens (6,11). In both allergic patients and nonatopic subjects, allergen-exposed BEC trigger the recruitment of monocyte-derived DC (MDDC) precursors through the secretion of CCL2, CCL5, and CXCL10.…”

Activation of Pulmonary Dendritic Cells and Th2-Type Inflammatory Responses on Instillation of Engineered, Environmental Diesel Emission Source or Ambient Air Pollutant Particles in vivo

“…Further, several lines of evidence have proposed that bronchial epithelial cells are targeted by respirable pollutants in much the same way as the abundant DC that interdigitate those epithelial cells and 'survey' the external environment [51][52][53] . It has been shown that ambient PM also induces epithelial cells to produce amphiregulin, granulocyte-macrophage colony-stimulating factor and MIP-3 ␣ [53][54][55][56] , that are known to induce recruitment and survival of DC.…”

Radioresistant cells expressing TLR5 control the respiratory epithelium's innate immune responses to flagellin

“…These data are corroborated by experiments on animals lacking the TRIF adaptor molecule used by TLR4. Hence, the flagellin-mediated lung innate response depends solely on the TLR5 receptor and the MyD88 adaptor.Airway epithelial cells also produce chemokines (such as CCL20) that attract monocytes/dendritic cells and that may potentiate adaptive immunity in a mucosal adjuvant mechanism [34,[51][52][53][54][55]. In contrast, flagellin may directly activate lung dendritic cells [48,56].…”