NOD1 and NOD2 regulation of pulmonary innate immunity to Legionella pneumophila.
The role of nucleotide-binding oligomerization domain-1 (NOD1) and nucleotide-binding oligomerization domain-2 (NOD2), cytoplasmic receptors which detect bacterial cell wall molecules, in pulmonary innate immune responses is poorly understood. We determined that both NOD1 and NOD2 detect heat-killed Legionella and stimulate NF-κb and IFN-β promoter activity using an in vitro luciferase reporter system. We next infected NOD1- and NOD2-deficient animals with aerosolized Legionella pneumophila. At 3 days post infection, Nod1(-/-) mice had impaired bacterial clearance compared to WT controls. In addition, at 4 h and 24 h, Nod1(-/-) mice had impaired neutrophil recruitment to the alveolar space. In contrast, increased lung neutrophils were seen in the Nod2(-/-) animals at 24 h. Analysis of cytokine production at 4 h post infection revealed a significant decrease in proinflammatory cytokines in the Nod1(-/-) animals when compared to WT animals. In contrast, increased 4-h proinflammatory cytokines were seen in the Nod2(-/-) animals. Furthermore, the lungs of both Nod1(-/-) and Nod2(-/-) mice had significantly increased pro-inflammatory cytokine levels at 24 h, suggesting possible suppressive roles for later stages of infection. Together, our data suggest that although both NOD1 and NOD2 can detect Legionella, these receptors modulate the in vivo pulmonary immune response differently.
University of Washington School of Medicine, Seattle, WA 98195-6523, USA. berring@uw.edu
William R
WR
Berrington
Ravi
R
Iyer
Richard D
RD
Wells
Kelly D
KD
Smith
Shawn J
SJ
Skerrett
Thomas R
TR
Hawn
D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics; D016952:Legionella pneumophila / Q000276:immunology* / Q000472:pathogenicity; D007877:Legionnaires' Disease / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D016899:Interferon-beta