Neuroinflammation resulting from bacterial infections is a complex process which can turn into a self-perpetuating inflammatory cascade. Resulting neuronal cell death may cause neurological disabilities and can eventually lead to death.
One major event in the neuroinflammatory cascade is the release of cytokines by the pathogens in the central nervous system (CNS), leading to an increased permeability of the blood brain barrier and the recruitment of peripheral immune cells such as neutrophils. Within the CNS, resident immune cells such as astrocytes and microglial cells can be further activated as they exhibit pattern recognition receptors (PRRs) that recognize certain molecular structures of pathogens.
One such PRR present in humans as well as in mice is the formyl peptide receptor (FPR); in mice, FPR1 and FPR2 are the two most important isoforms. It is known that FPRs can be activated by a broad range of structures, but in different ways: whereas diverse bacterial and viral structures are known to induce a pro-inflammatory response, the endogenous protein annexin A1 and its terminal fragment “Ac2-26” lead to an anti-inflammatory response.
To further elucidate the specific role of the FPR receptor and its agonist Ac2-26 in bacterial meningitis-associated neuroinflammation in mice, a group of researchers around first author Marvin Rüger investigated the extent of neuroinflammation resulting from pneumococcal meningitis with and without Ac2-26-treatment in wild type (wt) mice as well as in FPR1- and FPR2-deficient mice.
In the study, one essential experimental approach was the visualization of neutrophils, astrocytes and microglia by immunohistochemistry (IHC) in mice brain sections, followed by the acquisition of whole slide images with the Microvisioneer manualWSI software and the subsequent analysis of the obtained images; the higher the detection level of the above-mentioned immune cells in the relevant regions in the brain sections, the higher the pro-inflammatory activity. In addition to IHC, real-time reverse transcription PCR analyses were conducted.
In summary, based on these experiments, it could be shown that Ac2-26-treatment of wt-mice led to reduced pro-inflammatory immune response and an overall amelioration of meningitis, as less severe neutrophil infiltration and a reduced induction of glial cells were observed compared to non-treated mice. A similar protective effect of Ac2-26-treatment could be observed for FPR1-deficient mice, but not for FPR2-deficient mice, indicating that the potential anti-inflammatory properties of Ac2-26 are mediated via FPR2 in mice. Thus, the study elucidated promising approaches for new treatment options for pneumococcal meningitis.
Publication:
Marvin Rüger, Eugenia Kipp, Nadine Schubert, Nicole Schröder, Thomas Pufe, Matthias B. Stope, Markus Kipp, Christian Blume, Simone C. Tauber, Lars-Ove Brandenburg: The formyl peptide receptor agonist Ac2-26 alleviates neuroinflammation in a mouse model of pneumococcal meningitis, Journal of Neuroinflammation, 2020