Diesel Exhaust Particle-Exposed Human Bronchial Epithelial Cells Induce Dendritic Cell Maturation

Abstract

Increased exposure to air pollutants such as diesel exhaust particles (DEP) has been proposed as one mechanism to explain the rise in allergic disorders. However, the immunologic mechanisms by which DEP enhance allergic sensitization and asthma remain unclear. We hypothesized that DEP act as an adjuvant for immature dendritic cell (DC) maturation via its effect on airway epithelial cell-derived microenvironment for DC. Immature monocyte-derived DC (iMDDC) failed to undergo phenotypic (CD80, CD83, CD86) or functional (T cell activation) maturation in response to exposure to DEP (0.001–100 μg/ml). In contrast, primary cultures of human bronchial epithelial cells (HBEC) treated with DEP induced iMDDC phenotypic maturation (2.6 ± 0.1-fold increase in CD83 expression, n = 4, p < 0.05) and functional maturation (2.6 ± 0.2-fold increase in T cell activation, n = 4, p < 0.05). Functional maturation of iMDDC was induced by conditioned medium derived from DEP-treated HBEC, and was inhibited in cultures with DEP-treated HBEC and blocking Abs against GM-CSF, or GM-CSF-targeted small interfering RNA. These data suggest that DEP induce Ag-independent DC maturation via epithelial cell-DC interactions mediated by HBEC-derived GM-CSF. Although additional signals may be required for polarization of DC, these data suggest a novel mechanism by which environmental pollutants alter airway immune responses.

Urban particulate matter stimulation of human dendritic cells enhances priming of naive CD8 T lymphocytes

“…That such an effect is enhanced with GM‐CSF is in agreement with our current understanding for a pro‐inflammatory role for GM‐CSF in pollution‐induced lung disease 16, 18, 19. Although not the focus of this research, our finding of suppression of MHC class I expression by GM‐CSF is intriguing and deserves more detailed investigation in dedicated studies.…”

“…GM‐CSF is important for survival of DCs in non‐lymphoid tissue,25 and the action of GM‐CSF on pulmonary DCs is influential in lymphocyte responses in the lung 25, 26. Treatment of epithelial cells with diesel exhaust particles, a major component of UPM, is known to stimulate production of GM‐CSF that in turn promotes DC maturation and activation 18. It is therefore pertinent to consider the actions of UPM on CD8 priming in the context of the GM‐CSF‐rich pulmonary environment.…”

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

“…It seems likely therefore that DC will be among the first cells to sense and respond to inhaled PM, although the importance of bronchial/pulmonary epithelial cells cannot be overlooked. It is possible that exposure to PM disrupts the integrity of pulmonary epithelial cells and thereby releases inflammatory cytokines that activate DC and drive Th2-mediated allergic immunity as suggested by others [57,58] . An attractive mechanism responsible for DC activation by epithelial cells suggests release of granulocyte-macrophage colony-stimulating factor and thymic stromal lymphopoietin (TSLP) on exposure to particulate pollutants that may also involve oxidative stress and the generation of reactive oxygen species in the activation of pulmonary DC [11,42,54,57,59] .…”

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

“…For example, it has been demonstrated that epithelial cells in the gastric mucosa condition local DCs through the release of soluble mediators, resulting in a noninflammatory phenotype that is crucial for the maintenance of intestinal homeostasis (23). More recent studies of the lung microenvironment suggest that AECs may also condition fully differentiated DCs (24,25). However, there is no information available that relates specifically to the situation prevailing in conducting airway tissues, i.e., where incoming monocytes recruited by inflammatory stimuli undergo maturation into DCs within the epithelium itself.…”