AbstractsBiology & Animal Science

The innate immune response to pathogens in the lung is initiated after detection of microbial molecules (pathogen-associated molecular patterns, PAMPs) by pattern recognition receptors (PRRs). This immune response is vital for preserving lung function during pneumonia as it fights the invading microbes. An unrestricted PRR-mediated inflammation, however, can also lead to excessive tissue damage and the development of acute lung injury. Cellular injury leads to the release of so-called damage-associated molecular patterns (DAMPs), which play an important role in the regulation of sterile inflammation. In this study, the hypothesis was tested that DAMPs are released during Streptococcus pneumoniae infection and influence the antibacterial immune response during pneumonia. The data demonstrate that S. pneumoniae infection leads to the release of several DAMPs including uric acid, ATP, and IL-33 by macrophages, alveolar epithelial cells (AECs) and/or lung tissue. Experiments with specific knock-out mice, inhibitors and degrading enzymes revealed that uric acid, ATP, as well as several DAMP-recognizing receptors play a minor role in pneumococcal pneumonia. In contrast, IL-33 and its receptor ST2 negatively regulated the immune response to S. pneumoniae. St2-/- and Il33-/- mice were more resistant to pneumococcal pneumonia and showed increased bacterial clearance, reduced mortality, and enhanced integrity of the lung epithelial-endothelial barrier compared to wild-type animals. St2 and Il33 were found to be mainly expressed by AECs and endothelial cells. Interestingly, ST2 but not IL-33 negatively regulated KC production in AECs as well as neutrophil influx into the lung, whereas both molecules seemed to affect the recruitment of macrophages. Finally, ST2-expressing type 2 innate lymphoid cells appeared to be recruited to the lung during the resolution phase of pneumococcal pneumonia. In summary, this study demonstrates that IL-33 and ST2 differentially regulate the anti-pneumococcal innate immune response. The data suggest that IL-33 can act as a DAMP via ST2, and that both molecules can also have independent functions from each other. Die angeborene Immunantwort auf Infektionen in der Lunge basiert auf der Erkennung von konservierten mikrobiellen Molekülen (pathogen-associated molecular patterns, PAMPs) durch Mustererkennungsrezeptoren. Diese Immunantwort ist zur Bekämpfung eindringender Pathogene und zur Aufrechterhaltung der Lungenfunktion essentiell. Eine überschießende Entzündungsreaktion kann jedoch das Gewebe schädigen und ein akutes Lungenversagen hervorrufen. Durch zelluläre Schädigungen werden endogene, sogenannte damage associated molecular patterns (DAMPs) freigesetzt, die eine wichtige Rolle in der Regulation von sterilen Entzündungen spielen. In dieser Arbeit wurde die Hypothese getestet, dass DAMPs während der Pneumokokkeninfektion freigesetzt werden und die antibakterielle Immunantwort beeinflussen. Die Ergebnisse zeigen, dass die Infektion von Makrophagen, alveolären Epithelzellen und/oder…