期刊
INFECTION AND IMMUNITY
卷 88, 期 1, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/IAI.00678-19
关键词
Pseudomonas aeruginosa; Egr-1; inflammation
资金
- Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN-05446]
- Canadian Institutes of Health Research (CIHR) [MOP-68815]
- Cystic Fibrosis Canada Marsha Morton Early Career Investigator award
- Canada Foundation for Innovation John R. Evans Leaders Fund
Pseudomonas aeruginosa is an opportunistic pathogen that is a common cause of nosocomial infections. The molecular mechanisms governing immune responses to P. aeruginosa infection remain incompletely defined. Early growth response 1 (Egr-1) is a zinc-finger transcription factor that controls inflammatory responses. Here, we characterized the role of Egr-1 in host defense against P. aeruginosa infection in a mouse model of acute bacterial pneumonia. Egr-1 expression was rapidly and transiently induced in response to P. aeruginosa infection. Egr-1-deficient mice displayed decreased mortality, reduced levels of proinflammatory cytokines (tumor necrosis factor [INF], interleukin-1 beta [IL-1 beta], IL-6, IL-12, and IL-17), and enhanced bacterial clearance from the lung. Egr-1 deficiency caused diminished NF-kappa B activation in P. aeruginosa-infected macrophages independently of I kappa B alpha phosphorylation. A physical interaction between Egr-1 and NF-kappa B p65 was found in P. aeruginosa-infected macrophages, suggesting that Egr-1 could be required for assembly of heterodimeric transcription factors that direct synthesis of inflammatory mediators. Interestingly, Egr-1 deficiency had no impact on neutrophil recruitment in vivo due to its differential effects on chemokine production, which included diminished accumulation of KC (CXCL1), MIP2 (CXCL2), and IP-10 (CXCL10) and increased accumulation of LIX (CXCL5). Importantly, Egr-1-deficient macrophages and neutrophils displayed significant increases in nitric oxide production and bacterial killing ability that correlated with enhanced bacterial clearance in Egr-1-deficient mice. Together, these findings suggest that Egr-1 plays a detrimental role in host defense against P. aeruginosa acute lung infection by promoting systemic inflammation and negatively regulating the nitric oxide production that normally assists with bacterial clearance.
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