Einfluss des anti-inflammatorischen Liganden AC2-26 auf die Entzündungsreaktion in einem Streptococcus pneumoniae induzierten Meningitis-Maus-Modell

  • Role of the anti-inflammatory ligand AC2-26 on the inflammation in a mouse model of pneumococcal meningitis

Kipp, Eugenia; Brandenburg, Lars-Ove (Thesis advisor); Bohrmann, Johannes (Thesis advisor)

Aachen (2018, 2019)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2018

Abstract

Bacterial meningitis represents a severe infectious disease of the central nervous system. Although early antibiotic intervention is successfully provided to the patients, severe disease courses frequently occur. It is in our days widely accepted that the pathogenic cascades leading to those late clinical consequences do not principally involve the bacteria itself, but rather a sustained activation of the innate and adaptive immune response. Interference with such host immune responses is one novel strategy to ameliorated late clinical consequences after bacterial meningitis. One potential drug target is AC2-26, an active N-terminal peptide of Annexin A1. Results of several studies suggest that AC2-26 is a potent anti-inflammatory mediator under various experimental conditions. In this work, I aimed to analyze the effect of AC2-26 treatment in a murine model of bacterial meningitis. Both, in vitro and in vivo approaches were applied to investigate immunomodulatory properties of AC2-26. In vivo, overall mortality was just marginally affected by AC2-26 treatment. However, a sustained effect on glia cell activation was observed in AC2-26 treated groups. AC2-26 significantly prevented reactive astrogliosis and microgliosis and this effect was evident both, on the mRNA and protein level. Beyond, AC2-26 mediated suppression of microglia activation in the applied murine bacterial meningitis model was evident on the morphological level. While bacterial meningitis induced microglia hypertrophy and retraction of their fine processes, such morphological changes were less evident in AC2-26 meningitis mice. Furthermore, the recruitment of neutrophile granulocytes was less severe in AC2-26 treated groups. Finally, and in line with my in vitro data, AC2-26 ameliorated the expression induction on pro-inflammatory mediators, but promoted the expression of anti-inflammatory mediators, respectively. In summary, this thesis provides strong evidence that the active N-terminal peptide of Annexin A1, AC2-26, suppresses inflammatory cascades in a model of bacterial meningitis.

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