IFN regulatory factor 3 contributes to the host response during Pseudomonas aeruginosa lung infection in mice.
Pseudomonas aeruginosa is a major opportunistic pathogen. However, host defense mechanisms involved in P. aeruginosa lung infection remain incompletely defined. The transcription factor IFN regulatory factor 3 (IRF3) is primarily associated with host defense against viral infections, and a role of IRF3 in P. aeruginosa infection has not been reported previously. In this study, we showed that IRF3 deficiency led to impaired clearance of P. aeruginosa from the lungs of infected mice. P. aeruginosa infection induced IRF3 translocation to the nucleus, activation of IFN-stimulated response elements (ISRE), and production of IFN-beta, suggesting that P. aeruginosa activates the IRF3-ISRE-IFN pathway. In vitro, macrophages from IRF3-deficient mice showed complete inhibition of CCL5 (RANTES) and CXCL10 (IP-10) production, partial inhibition of TNF, but no effect on CXCL2 (MIP-2) or CXCL1 (keratinocyte-derived chemokine) in response to P. aeruginosa stimulation. In vivo, IRF3-deficient mice showed complete inhibition of CCL5 production and partial or no effects on production of other cytokines and chemokines in the bronchoalveolar lavage fluids and lung tissues. Profiling of immune cells in the airways revealed that neutrophil and macrophage recruitment into the airspace was reduced, whereas B cell, T cell, NK cell, and NKT cell infiltration was unaffected in IRF3-deficient mice following P. aeruginosa lung infection. These data suggest that IRF3 regulates a distinct profile of cytokines and chemokines and selectively modulates neutrophil and macrophage recruitment during P. aeruginosa infection. Thus, IRF3 is an integral component in the host defense against P. aeruginosa lung infection.
Carrigan
Svetlana O
SO
Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
Junkins
Robert
R
Yang
Yong Jun
YJ
Macneil
Adam
A
Richardson
Christopher
C
Johnston
Brent
B
Lin
Tong-Jun
TJ
D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D018920:Coculture Techniques; D003550:Cystic Fibrosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D007113:Immunity, Innate / Q000235:genetics; D050838:Interferon Regulatory Factor-3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D011552:Pseudomonas Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D020218:Response Elements / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
D018925:Chemokines; D016207:Cytokines; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse