Effects of mannose-binding lectin on pulmonary gene expression and innate immune inflammatory response to ozone.
Ozone is a common, potent oxidant pollutant in industrialized nations. Ozone exposure causes airway hyperreactivity, lung hyperpermeability, inflammation, and cell damage in humans and laboratory animals, and exposure to ozone has been associated with exacerbation of asthma, altered lung function, and mortality. The mechanisms of ozone-induced lung injury and differential susceptibility are not fully understood. Ozone-induced lung inflammation is mediated, in part, by the innate immune system. We hypothesized that mannose-binding lectin (MBL), an innate immunity serum protein, contributes to the proinflammatory events caused by ozone-mediated activation of the innate immune system. Wild-type (Mbl(+/+)) and MBL-deficient (Mbl(-/-)) mice were exposed to ozone (0.3 ppm) for up to 72 h, and bronchoalveolar lavage fluid was examined for inflammatory markers. Mean numbers of eosinophils and neutrophils and levels of the neutrophil attractants C-X-C motif chemokines 2 [Cxcl2 (major intrinsic protein 2)] and 5 [Cxcl5 (limb expression, LIX)] in the bronchoalveolar lavage fluid were significantly lower in Mbl(-/-) than Mbl(+/+) mice exposed to ozone. Using genome-wide mRNA microarray analyses, we identified significant differences in transcript response profiles and networks at baseline [e.g., nuclear factor erythroid-related factor 2 (NRF2)-mediated oxidative stress response] and after exposure (e.g., humoral immune response) between Mbl(+/+) and Mbl(-/-) mice. The microarray data were further analyzed to discover several informative differential response patterns and subsequent gene sets, including the antimicrobial response and the inflammatory response. We also used the lists of gene transcripts to search the LINCS L1000CDS(2) data sets to identify agents that are predicted to perturb ozone-induced changes in gene transcripts and inflammation. These novel findings demonstrate that targeted deletion of Mbl caused differential levels of inflammation-related gene sets at baseline and after exposure to ozone and significantly reduced pulmonary inflammation, thus indicating an important innate immunomodulatory role of the gene in this model.
Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina;
Jonathan M
JM
Ciencewicki
Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina;
Kirsten C
KC
Verhein
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina; and.
Kevin
K
Gerrish
Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina;
Zachary R
ZR
McCaw
Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
Jianying
J
Li
Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
Pierre R
PR
Bushel
Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina; kleeber1@niehs.nih.gov.
Steven R
SR
Kleeberger
D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D063990:Gene Ontology; D007113:Immunity, Innate; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008297:Male; D037601:Mannose-Binding Lectin / Q000502:physiology*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010126:Ozone / Q000633:toxicity*; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism; D060066:Protein Interaction Maps; D059467:Transcriptome
D000393:Air Pollutants; D037601:Mannose-Binding Lectin; D010126:Ozone
genome-wide transcriptomics; innate immunity; neutrophils; pattern recognition analysis; tumor necrosis factor-α