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An Essential Role for Non–Bone Marrow–Derived Cells in Control of Pseudomonas aeruginosa Pneumonia

Departments of Immunology, Comparative Medicine, and Medicine, University of Washington School of Medicine, Seattle, Washington

Correspondence and requests for reprints should be addressed to Adeline M. Hajjar, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195. E-mail: hajjar{at}u.washington.edu

MyD88 is an adapter protein required for the induction of proinflammatory cytokines by most Toll-like receptors (TLR), and Pseudomonas aeruginosa expresses ligands for multiple TLRs. MyD88^–/– (KO) mice are highly susceptible to aerosolized P. aeruginosa, failing to elicit an early inflammatory response and permitting a 3-log increase in bacterial CFU in the lungs by 24 h after infection. We hypothesized that alveolar macrophages are the first cells to recognize and kill aerosolized P. aeruginosa in an MyD88-dependent fashion due to their location within the airways. To determine which cells in the lungs mediate MyD88-dependent defenses against P. aeruginosa, we generated radiation bone marrow (BM) chimeras between MyD88KO and wild-type (WT) mice. MyD88KO mice transplanted with MyD88KO BM (MyD88KOMyD88KO mice) displayed uncontrolled bacterial replication, whereas all other chimeras controlled the infection by 24 h. However, at 4 h, both MyD88KOMyD88KO and WTMyD88KO mice permitted intrapulmonary bacterial replication, whereas MyD88KOWT and WTWT mice did not, indicating that the source of BM had little impact on the early control of infection. Similarly, the genotype of the recipient rather than that of the BM donor determined early neutrophil recruitment to the lungs. Whereas intrapulmonary TNF- and IL-1 production were associated with WT BM, levels of the CXC chemokines MIP-2 and KC as well as GM-CSF were associated with recipient genotype. We conclude that lung parenchymal and BM-derived cells collaborate in the MyD88-dependent response to P. aeruginosa infection in the lungs in mice.

Key Words: alveolar macrophages • lung parenchyma • MyD88 • neutrophils • Pseudomonas aeruginosa • Toll-like receptors

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