p47phox deficiency induces macrophage dysfunction resulting in progressive crystalline macrophage pneumonia.
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-gamma), 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.
Liu
Qi
Q
Monocyte Trafficking Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1456, USA.
Cheng
Lily I
LI
Yi
Liang
L
Zhu
Nannan
N
Wood
Adam
A
Changpriroa
Cattlena May
CM
Ward
Jerrold M
JM
Jackson
Sharon H
SH
D000818:Animals; D015153:Blotting, Western; D002688:Chitinases / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006105:Granulomatous Disease, Chronic / Q000276:immunology* / Q000473:pathology; D007150:Immunohistochemistry; D037102:Lectins / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D019255:NADPH Oxidases / Q000172:deficiency* / Q000276:immunology / Q000378:metabolism; D011014:Pneumonia / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D037102:Lectins; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D002688:Chitinases; C525260:Ym2 protein, mouse; C429541:Chil3 protein, mouse; D001619:beta-N-Acetylhexosaminidases