TREM-1 improves the inflammatory response and outcome to Streptococcus pneumoniae infection by reducing levels of negative regulators in the lung
Abstract number: S69
Lagler H., Sharif O., Haslinger I., Matt U., Stich K., Furtner T., Schmidt K., Knapp S.
Background: Triggering receptor expressed on myeloid cells (TREM-1) is a cell surface receptor present on both monocytes/macrophages and neutrophils that has been shown to amplify cytokine and chemokine production in response to bacterial Toll like receptor (TLR) ligands. Blocking studies revealed TREM-1 as a valuable target to prevent overwhelming inflammation during sepsis. At the same time, TREM-1 is highly expressed within the pulmonary compartment with soluble TREM-1 being a valuable marker indicating the presence of pneumonia in humans. The biological role of TREM-1 during community acquired pneumonia, such as pneumococcal pneumonia is not known. The aim of the present study was to determine the function of TREM-1 in the inflammatory response to Streptococcus pneumoniae infection in vivo, the mechanism where by this occurred, and the outcome of this on infection.
Methods: C57BL/6 mice were intranasally infected with S. pneumoniae followed by i.p. treatment with PBS, isotype Ab or agonistic TREM-1 mAb. Bacterial counts, lung histology, neutrophil influx, chemokine/cytokine responses and signaling mediators as well as survival were evaluated in vivo in a time dependent manner. In vitro, immortalised lung alveolar macrophages (MHS) and respiratory epithelial cells were utilised to study the response to S. pneumoniae treatment.
Results: Mice pre-treated with agonistic TREM-1 displayed a significantly amplified cytokine and chemokine responses (TNF, MIP-2 and IL-6) as well as neutrophil influx to the lungs 6h after induction of pneumonia. This enhanced early inflammation was associated with lower numbers of bacteria in the lungs and reduced pulmonary inflammation at 48hr, resulting in improved survival. In vitro studies corroborated these results at the early time point. A reduction of negative regulators of TLR signaling in lungs was observed in mice pre-treated with TREM-1 in vivo.
Conclusion: TREM-1 boosts the early inflammatory response during S. pneumoniae infection in vivo through lowering levels of negative regulators in the lung, which results in accelerated bacterial clearance and ultimately improved survival.
|Session name:||18th European Congress of Clinical Microbiology and Infectious Diseases|
|Back to top|