The formyl peptide receptor agonist Ac2-26 alleviates neuroinflammation in a mouse model of pneumococcal meningitis

Abstract

Background Bacterial meningitis is still a cause of severe neurological disability. The brain is protected from penetrating pathogens by the blood-brain barrier and the innate immune system. The invading pathogens are recognized by pattern recognition receptors including the G-protein-coupled formyl peptide receptors (FPRs), which are expressed by immune cells of the central nervous system. FPRs show a broad spectrum of ligands, including pro- and anti-inflammatory ones. Here, we investigated the effects of the annexin A1 mimetic peptide Ac2-26 in a mouse model of pneumococcal meningitis. Methods Wildtype (WT) and Fpr1- and Fpr2-deficient mice were intrathecally infected with Streptococcus pneumoniae D39 (type 2). Subsequently, the different mice groups were treated by intraperitoneal injections of Ac2-26 (1 mg/kg body weight) 2, 8, and 24 h post-infection. The extent of inflammation was analyzed in various brain regions by means of immunohistochemistry and real-time reverse transcription polymerase chain reaction (RT-PCR) 30 h post-infection. Results Ac2-26-treated WT mice showed less severe neutrophil infiltration, paralleled by a reduced induction of pro-inflammatory glial cell responses in the hippocampal formation and cortex. While meningitis was ameliorated in Ac2-26-treated Fpr1-deficient mice, this protective effect was not observed in Fpr2-deficient mice. Irrespective of Ac2-26 treatment, inflammation was more severe in Fpr2-deficient compared to Fpr1-deficient mice. Conclusions In summary, this study demonstrates anti-inflammatory properties of Ac2-26 in a model of bacterial meningitis, which are mediated via FPR2, but not FPR1. Ac2-26 and other FPR2 modulators might be promising targets for the development of novel therapies for Streptococcus pneumoniae-induced meningitis.

Annexin A1 protects against cerebral ischemia–reperfusion injury by modulating microglia/macrophage polarization via FPR2/ALX-dependent AMPK-mTOR pathway

“…When binding to endogenous antiinflammatory/pro-resolving ligands (e.g., specialized proresolving lipid mediators lipoxin A4 and resolvin D1, and ANXA1) or pro-inflammatory ligands (e.g., formylated bacterial peptides and amyloid beta), FPR2/ALX receptor is activated and triggers downstream signaling cascades and subsequent distinct anti-or proinflammatory responses [50,51]. The immune regulation roles of ANXA1 and Ac2-26 through functional interaction with FPR2/ALX receptor have been reported using pharmacological and genetic approaches [36,[52][53][54]. In the current study, we utilized the specific FPR2/ ALX antagonist WRW4 and confirmed that Ac2-26 could bias the surface FPR2/ALX receptor of microglia/ macrophages to mediate phenotype polarization and inflammatory responses both in vivo and in vitro.…”

The Role of Formyl Peptide Receptors in Neurological Diseases via Regulating Inflammation

“…FPR deficiency is associated with increased bacterial burden and infiltration of the CNS by neutrophils and granulocytes, with distinct changes of the inflammatory immune reaction, resulting in higher mortality rates ( Oldekamp et al, 2014 ). Recent research has indicated that the anti-inflammatory effect also applies to meningitis ( Ruger et al, 2020 ). Another study using a mouse model of Streptococcus suis -induced meningitis, indicated that AnxA1 exerted anti-inflammatory effects via attenuating leukocyte infiltration, inflammatory mediator production, and astrocyte or microglial activation in the brain, along with decreasing neutrophil adherence to the endothelium through FPR2, thus inhibiting meningitis progression.…”

Identification of hub genes and immune cell infiltration characteristics in chronic rhinosinusitis with nasal polyps: Bioinformatics analysis and experimental validation

“…To date, no studies have reported the involvement of these genes in the occurrence and development of CRSwNP. A recent study has confirmed that the formyl peptide receptor agonist Ac2-26 exerts an anti-inflammatory effect in a mouse model of bacterial meningitis through the formamide peptide receptor 2 ( FPR2 ) ( Rüger et al, 2020 ). FPR2 agonists could stimulate the resolution of inflammation by inhibiting neutrophil chemotaxis and stimulating macrophage phagocytosis, which may be the key to the treatment of chronic inflammatory diseases ( Asahina et al, 2020 ).…”