p47phox Deficiency Induces Macrophage Dysfunction Resulting in Progressive Crystalline Macrophage Pneumonia

Nicotinamide dinucleotide phosphate oxidase-deficient (p47phox−/−) mice are a model of human chronic granulomatous disease; these mice are prone to develop systemic infections and inflammatory diseases. The use of antibiotic (Bactrim) prophylaxis in a specific pathogen-free environment, however, impedes infection in the majority of p47phox−/− mice. We examined infection-free p47phox−/− mice between 1 and 14 months of age and found that they developed proliferative macrophage lesions containing Ym1/Ym2 protein and crystals in lung, bone marrow, lymph nodes, and spleen. Here, we show that the lung lesions progressed from single macrophages with intracellular Ym1/Ym2 protein crystals to severe diffuse crystalline macrophage pneumonia without histological evidence of either granulation tissue or pulmonary fibrosis. Ym1/Ym2 is a chitinase-like secretory protein that is transiently induced in alternatively activated macrophages during T-helper (Th)2-biased pathogenesis and during chemical and traumatic inflammation. Bronchoalveolar lavage from p47phox−/− mice contained significantly higher levels of Th-1 (interferon-γ), Th-2 (interleukin-4), and Th-17 (interleukin-17)-associated cytokines than wild-type mice, as well as copious amounts of interleukin-12, indicating that Ym1-secreting p47phox−/− macrophages are also integrated into classically activated macrophage responses. These results suggest that p47phox−/− macrophages are extremely pliable, due in part to an intrinsic dysfunction of macrophage activation pathways that allows for distinct classical or alternative activation phenotypes.