Cell Specific Innate Immunity In Lung Infection And Inflammation

"Pneumonia and asthma affect millions of adults and children annually and are responsible for a significant amount of morbidity and mortality worldwide. Our airways are continuously exposed to pathogens and allergens inhaled through air that can potentially cause these serious illnesses. The innate immune system is initiated once the epithelial barrier fails. The net effect of the innate immunity is the result of complex cell-specific responses not yet fully understood. In this thesis, we studied these cell-specific contributions to host defense using genetically modified mice in which bacterial pneumonia and asthma were simulated. Cells present in the respiratory tract are able to recognize specific molecular patterns of pathogens or allergens because of the expression Toll-like receptors (TLRs). Correct functioning of TLRs is regulated by the chaperone glycoprotein 96 (gp96), and we found that host defense of mice with gp96 deficient macrophages was strongly impaired during pneumonia caused by Klebsiella pneumoniae. Next, we studied the cell-specific role of myeloid differentiation factor 88 (MyD88), the universal adaptor protein found downstream in the TLR signaling pathway. In a series of studies, we found that only myeloid MyD88, but not endothelial or epithelial MyD88, contributes significantly to protection against Klebsiella pneumonia, while in pneumonia induced by Pseudomonas Aeruginosa, antibacterial defense depends on epithelial but not myeloid MyD88. Finally, we examined the role of cell-specific MyD88 signaling in asthma, and found that general expression of MyD88 is essential for the development of asthma. Neither myeloid nor alveolar type II MyD88 affects asthma induced inflammatory response."--Samenvatting auteur.