Lung epithelial MyD88 drives early pulmonary clearance of Pseudomonas aeruginosa by a flagellin dependent mechanism.
Pseudomonas aeruginosa is a flagellated pathogen frequently causing pneumonia in hospitalized patients and sufferers of chronic lung disease. Here we investigated the role of the common Toll-like receptor (TLR) adaptor myeloid differentiation factor (MyD)88 in myeloid vs. lung epithelial cells in clearance of P. aeruginosa from the airways. Mice deficient for MyD88 in lung epithelial cells (Sftpccre-MyD88-lox mice) or myeloid cells (LysMcre-MyD88-lox mice) and bone marrow chimeric mice deficient for TLR5 (the receptor recognizing Pseudomonas flagellin) in either parenchymal or hematopoietic cells were infected with P. aeruginosa via the airways. Sftpccre-MyD88-lox mice demonstrated a reduced influx of neutrophils into the bronchoalveolar space and an impaired early antibacterial defense after infection with P. aeruginosa, whereas the response of LysMcre-MyD88-lox mice did not differ from control mice. The immune-enhancing role of epithelial MyD88 was dependent on recognition of pathogen-derived flagellin by epithelial TLR5, as demonstrated by an unaltered clearance of mutant P. aeruginosa lacking flagellin from the lungs of Sftpccre-MyD88-lox mice and an impaired bacterial clearance in bone marrow chimeric mice lacking TLR5 in parenchymal cells. These data indicate that early clearance of P. aeruginosa from the airways is dependent on flagellin-TLR5-MyD88-dependent signaling in respiratory epithelial cells.
Center of Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Center of Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; a.a.anas@amc.uva.nl.
Adam A
AA
Anas
Center of Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Center of Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
Miriam H P
MH
van Lieshout
Center of Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Center of Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
Theodora A M
TA
Claushuis
Center of Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Center of Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
Alex F
AF
de Vos
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
Sandrine
S
Florquin
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
Onno J
OJ
de Boer
Key Laboratory of Infection and Immunity, Institute of Biophysics, Chaoyang District, Beijing, China; and.
Baidong
B
Hou
Center of Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Center of Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
Cornelis
C
Van't Veer
Center of Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Center of Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Tom
T
van der Poll
D056809:Alveolar Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D000818:Animals; D005408:Flagellin / Q000276:immunology; D007113:Immunity, Innate; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D020556:Neutrophil Infiltration; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D011552:Pseudomonas Infections / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D015398:Signal Transduction; D051198:Toll-Like Receptor 5 / Q000378:metabolism
C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051198:Toll-Like Receptor 5; D005408:Flagellin
MyD88; Pseudomonas; TLR; lung epithelial; pneumonia