Published online before print December 18, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: ajpath.2009.080555v1 174/1/153    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Liu, Q. Articles by Jackson, S. H. Search for Related Content PubMed PubMed Citation Articles by Liu, Q. Articles by Jackson, S. H.

(American Journal of Pathology. 2009;174:153-163.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080555

p47^phox Deficiency Induces Macrophage Dysfunction Resulting in Progressive Crystalline Macrophage Pneumonia

Qi Liu^*, Lily I. Cheng, Liang Yi^*, Nannan Zhu^*, Adam Wood^*, Cattlena May Changpriroa^*, Jerrold M. Ward and Sharon H. Jackson^*

From the Monocyte Trafficking Unit,^* Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Infectious Disease Pathogenesis Section, Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

Nicotinamide dinucleotide phosphate oxidase-deficient (p47^phox–/–) 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 p47^phox–/– mice. We examined infection-free p47^phox–/– 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 p47^phox–/– mice contained significantly higher levels of Th-1 (interferon-), 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 p47^phox–/– macrophages are also integrated into classically activated macrophage responses. These results suggest that p47^phox–/– macrophages are extremely pliable, due in part to an intrinsic dysfunction of macrophage activation pathways that allows for distinct classical or alternative activation phenotypes.