Conventional DC specific CSF1R depletion represents the reduction of the alveolar cDC2 and attenuation of allergic lung inflammation

Abstract

Abstract Dendritic cells play a key role in sensing aeroallergen and initiating Th2 immune reaction in asthma by bridging between innate and adaptive immune responses. Among the DC subtypes, conventional DC2 (cDC2) has been known to be a major player in developing allergic asthma. We recently reported that airway epithelial cell-derived CSF1 significantly promotes allergic sensitization through activating alveolar CSF1R+ cDC2 resulting in enhanced allergen-specific IgE production and subsequent Th2 immune response. This finding highlights the fundamental role of cDC2 in allergen sensitization. However, studying cDC2 has been hindered by the lack of available cDC2 specific-Cre mouse. Since CSF1R promoter activity is relatively enhanced in cDC2, we generated Zbtb46-cre;Csf1rfl/fl mice (hereafter CSF1RΔcDC) by crossbreeding cDC specific Zbtb46-cre and CSF1R flox mice. Of interest, we found that CSF1RΔcDC has a significant reduction in cDC2 population in alveolar space compared to Zbtb46-cre mice, whereas cDC1 and cDC2 in the lung and cDC1 in alveolar space were not affected in the steady state. When the mice were subjected to the allergen challenge, the number of cDC2 migrating to regional lymph node with carrying the allergen was markedly diminished in CSF1RΔcDC mice. Subsequently, the production of total and allergen-reactive IgE was blocked and allergic lung inflammation including eosinophil recruitment was attenuated in CSF1RΔcDC mice, compared to control littermate mice. These data suggest that CSF1RΔcDC mice are suitable to investigate the specific role of cDC2 in alveolar space and CSF1R+ cDC2 in alveolar space plays a key role in allergen sensitization and asthma development.