title: Regulator of calcineurin 1 suppresses inflammation during respiratory tract infections.
abstract: Respiratory tract infection with Pseudomonas aeruginosa is a common cause of hospitalization in immune-compromised individuals. However, the molecular mechanisms involved in the immune response to P. aeruginosa lung infection remain incompletely defined. In this study, we demonstrate that the regulator of calcineurin 1 (RCAN1) is a central negative regulator of inflammation in a mouse model of acute bacterial pneumonia using the opportunistic bacterial pathogen P. aeruginosa. RCAN1-deficient mice display greatly increased mortality following P. aeruginosa lung infection despite enhanced neutrophil recruitment and bacterial clearance. This mortality is associated with higher systemic levels of proinflammatory cytokines in RCAN1-deficient animals. These aberrant inflammatory responses coincide with increased transcriptional activity of proinflammatory RCAN1-target proteins NFAT and NF-κB. In addition, we reveal a novel regulatory role for RCAN1 in the ERK/STAT3 pathway both in vitro and in vivo, suggesting that aberrant STAT3 activity may significantly contribute to delayed resolution of inflammatory responses in our model. Together, these findings demonstrate that RCAN1 is a potent negative regulator of inflammation during respiratory tract infections.
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Junkins
authors.forename: Adam J
authors.initials: AJ
authors.lastname: MacNeil
authors.forename: Zhengli
authors.initials: Z
authors.lastname: Wu
authors.forename: Craig
authors.initials: C
authors.lastname: McCormick
authors.forename: Tong-Jun
authors.initials: TJ
authors.lastname: Lin
mesh_terms: D000818:Animals; D058491:Bacterial Load; D019703:Calcineurin / Q000378:metabolism; D002135:Calcium-Binding Proteins; D016207:Cytokines / Q000097:blood; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D050778:NFATC Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000382:microbiology; D011552:Pseudomonas Infections / Q000276:immunology* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D016207:Cytokines; C511512:DSCR1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D019703:Calcineurin