Alveolar macrophages regulate granulomatous inflammation in a mouse model of chronic beryllium disease.

Abstract

Abstract Chronic beryllium disease is a granulomatous lung disease orchestrated by beryllium-specific CD4+ Th1 cells. In addition to its role as a pathogenic antigen, beryllium has potent effects on innate immune cells. In mice, beryllium exposure causes cellular death and release of alarmins, including IL-1α and DNA. This is associated with accelerated migration of pulmonary dendritic cells from the lung to the draining lymph nodes, upregulation of costimulatory molecules on their surfaces and enhanced priming of effector Th1 cells. These effects are MyD88-dependent but independent of the inflammasome. Our previous characterization of a mouse model of berylliosis showed that in contrast to WT mice, HLA-DP2 transgenic mice exposed to beryllium develop beryllium-specific Th1 responses and peribronchovascular infiltrates in the lung. We wanted to investigate the role of alveolar macrophages in this model using depletion with clodronate liposomes. Intratracheal instillation of mice with clodronate liposomes depleted alveolar macrophages but dendritic cell migration to the draining lymph nodes remained intact. HLA-DP2 transgenic mice depleted of alveolar macrophages generated beryllium-specific Th1 responses in both lung and spleen that were similar to those in mice treated with control PBS-containing liposomes. Surprisingly, however, the depletion of alveolar macrophages severely exacerbated the development of granulomas in the lung. These results implicate alveolar macrophages in regulating granulomatous inflammation in the lung.