Reversal of β-Amyloid-Induced Microglial Toxicity In Vitro by Activation of Fpr2/3

Abstract

Microglial inflammatory activity is thought to be a major contributor to the pathology of neurodegenerative conditions such as Alzheimer’s disease (AD), and strategies to restrain their behaviour are under active investigation. Classically, anti-inflammatory approaches are aimed at suppressing proinflammatory mediator production, but exploitation of inflammatory resolution, the endogenous process whereby an inflammatory reaction is terminated, has not been fully investigated as a therapeutic approach in AD. In this study, we sought to provide proof-of-principle that the major proresolving actor, formyl peptide receptor 2, Fpr2, could be targeted to reverse microglial activation induced by the AD-associated proinflammatory stimulus, oligomeric β-amyloid (oAβ). The immortalised murine microglial cell line BV2 was employed as a model system to investigate the proresolving effects of the Fpr2 ligand QC1 upon oAβ-induced inflammatory, oxidative, and metabolic behaviour. Cytotoxic behaviour of BV2 cells was assessed through the use of cocultures with retinoic acid-differentiated human SH-SY5Y cells. Stimulation of BV2 cells with oAβ at 100 nM did not induce classical inflammatory marker production but did stimulate production of reactive oxygen species (ROS), an effect that could be reversed by subsequent treatment with the Fpr2 ligand QC1. Further investigation revealed that oAβ-induced ROS production was associated with NADPH oxidase activation and a shift in BV2 cell metabolic phenotype, activating the pentose phosphate pathway and NADPH production, changes that were again reversed by QC1 treatment. Microglial oAβ-stimulated ROS production was sufficient to induce apoptosis of bystander SH-SY5Y cells, an effect that could be prevented by QC1 treatment. In this study, we provide proof-of-concept data that indicate exploitation of the proresolving receptor Fpr2 can reverse damaging oAβ-induced microglial activation. Future strategies that are aimed at restraining neuroinflammation in conditions such as AD should examine proresolving actors as a mechanism to harness the brain’s endogenous healing pathways and limit neuroinflammatory damage.

Near-infrared light reduces β-amyloid-stimulated microglial toxicity and enhances survival of neurons: mechanisms of light therapy for Alzheimer’s disease

“…In the present study, we aimed to determine the potential of light as a tool for controlling microglial inflammation caused by toxic oligomeric Aβ [ 63 ]. The Aβ concentration of 1 μM was used, which caused both an increase of pro-inflammatory cytokine secretion and ROS generation, in contrast to nanomolar concentrations, which do not cause an inflammatory response in vitro [ 64 ].…”

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

“…The pathologies underlying protein misfolding are many, and misfolded proteins are host-derived proteins that induce FPR-activation, particularly FPR2. A familiar amyloidogenic protein associated with an FPR2 agonist is amyloid-β 1-42 (Aβ1-42), a well-documented peptide fragment in patients with Alzheimer’s disease (AD) ( Wickstead et al, 2020 ), and the prion protein fragment PrP (106-126), which interacts with FPRs on astrocytes and microglia and regulates inflammatory process such as calcium mobilization, chemotaxis, and the production of pro-inflammatory cytokines ( Le et al, 2001b ). AnxA1, LXA4, and RvD1 are regarded as endogenous pro-resolving FPR ligands.…”

“…The oAβ-induced production of ROS may be associated with nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, pentose phosphate pathway activation, and NADPH production, with changes that were reversed by mFPR2 ligand treatment. Microglial oAβ-stimulated ROS production could reportedly induce cell apoptosis, which could be prevented by mFPR2 ligand treatment, suggesting potential targets for therapeutic interventions ( Wickstead et al, 2020 ). Thus, as a receptor for Aβ, FPR2 could remove Aβ, which has possible protective effects in the AD-brain.…”

Time-Dependent Protective and Pro-Resolving Effects of FPR2 Agonists on Lipopolysaccharide-Exposed Microglia Cells Involve Inhibition of NF-κB and MAPKs Pathways

“…According to current views, inflammation is a multistage self-resolving process mediated by various factors that "switch off" the inflammatory response [17]. Nevertheless, disturbances in the resolution of inflammation (RoI) [18,19] can be involved in the pathogenesis of brain-related inflammatory diseases, mainly due to the constant stimulation of the immune system, overproduction of pro-inflammatory cytokines, oxidative stress, and potential impairment in the maintenance of homeostasis [20][21][22][23].…”