| The lung employs a plethora of defenses to protect against invading pathogens and maintain proper respiratory function. While there are a number of professional immune cells resident in the lung, the respiratory epithelium itself is pivotal in recognizing, coordinating, and mounting an appropriate immune response. TLR2 on the surface of the airway epithelium is capable of recognizing cell wall components of inhaled bacteria such as Pseudomonas aeruginosa . Receptor ligation elicits the transient release of intracellular Ca2+ that drives subsequent NFkappaB activation and production of proinflammatory chemokines and cytokines such as CXCL8. We found that this TLR2 induced Ca2+ signal could be transmitted to adjacent naive cells via gap junctions, thus amplifying epithelial production of CXCL8. Subsequent to receptor ligation, TLR2 also caused the phosphorylation of Cx43 and drove its association with c-Src, events linked to channel closure. These events coincided with decreased epithelial gap junction communication and demonstrate a novel regulatory mechanism for TLR induced proinflammatory signaling. In additon to epithelial to epithelial communication, we also characterized the induction of airway epithelial type I interferon production in response to an extracellular pathogen, Staphylococcus aureus, that elicited dramatic effects on lung dendritic cells Type I IFN production was dependent on expression of staphylococcal protein A (SpA) and required host expression of the TRIF adaptor protein. Mice lacking the common Interferon alpha/beta receptor (IFNAR) exhibited dramatic protection from staphylococcal pneumonia, indicating that this signaling pathway increases susceptibility to the organism. This protection was accompanied by increased numbers of respiratory dendritic cells. Depletion experiments subsequently demonstrated that both alveolar macrophages and respiratory dendritic cells were required to support normal host responses to staphylococcal infection. The importance of these two cell types was further verified utilizing a newly developed model of staphylococcal superinfection after H1N1 Influenza A infection. Depletion of CD11c + cells due to H1N1 significantly increased the host susceptibility to staphylococcal infection. This work demonstrates two novel routes of epithelial communication, epithelial to epithelial and epithelial to CD11c+ cell, that are absolutely required for the response to the common respiratory pathogens P. aeruginosa and S. aureus. |
