Increased susceptibility to pulmonary Pseudomonas infection in Splunc1 knockout mice.
The airway epithelium is the first line of host defense against pathogens. The short palate, lung, and nasal epithelium clone (SPLUNC)1 protein is secreted in respiratory tracts and is a member of the bacterial/permeability increasing (BPI) fold-containing protein family, which shares structural similarities with BPI-like proteins. On the basis of its homology with BPIs and restricted expression of SPLUNC1 in serous cells of submucosal glands and surface epithelial cells of the upper respiratory tract, SPLUNC1 is thought to possess antimicrobial activity in host defense. SPLUNC1 is also reported to have surfactant properties, which may contribute to anti-biofilm defenses. The objective of this study was to determine the in vivo functions of SPLUNC1 following Pseudomonas aeruginosa infection and to elucidate the underlying mechanism by using a knockout (KO) mouse model with a genetic ablation of Splunc1. Splunc1 KO mice showed accelerated mortality and increased susceptibility to P. aeruginosa infection with significantly decreased survival rates, increased bacterial burdens, exaggerated tissue injuries, and elevated proinflammatory cytokine levels as compared with those of their wild-type littermates. Increased neutrophil infiltration in Splunc1 KO mice was accompanied by elevated chemokine levels, including Cxcl1, Cxcl2, and Ccl20. Furthermore, the expression of several epithelial secretory proteins and antimicrobial molecules was considerably suppressed in the lungs of Splunc1 KO mice. The deficiency of Splunc1 in mouse airway epithelium also results in increased biofilm formation of P. aeruginosa. Taken together, our results support that the ablation of Splunc1 in mouse airways affects the mucociliary clearance, resulting in decreased innate immune response during Pseudomonas-induced respiratory infection.
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15260;
Yanyan
Y
Liu
Marissa E
ME
Di
Hong Wei
HW
Chu
Xinyu
X
Liu
Ling
L
Wang
Sally
S
Wenzel
Y Peter
YP
Di
D000818:Animals; D058491:Bacterial Load / Q000276:immunology; D018441:Biofilms / Q000254:growth & development; D054418:Chemokine CCL20 / Q000096:biosynthesis; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D006023:Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D011552:Pseudomonas Infections / Q000276:immunology* / Q000401:mortality; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D020545:Respiratory Mucosa / Q000276:immunology / Q000382:microbiology; D012141:Respiratory Tract Infections / Q000276:immunology* / Q000378:metabolism; D015996:Survival Rate
C119074:Bpifa1 protein, mouse; C493447:CCL20 protein, mouse; D054418:Chemokine CCL20; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D016207:Cytokines; D006023:Glycoproteins; D010750:Phosphoproteins