Emerging contributions of formyl peptide receptors to neurodegenerative diseases.

Lukas Busch,Bernd Bufe,Kristina Endres,Susan Brödel,Stefan Vieten

doi:10.1515/hsz-2021-0258

Abstract

Inflammation is a central element of many neurodegenerative diseases. Formyl peptide receptors (FPRs) can trigger several receptor-dependent signal transduction pathways that play a key role in neuroinflammation and neurodegeneration. They are chemotactic receptors that help to regulate pro- and anti-inflammatory responses in most mammals. FPRs are primarily expressed in the immune and nervous systems where they interact with a complex pattern of pathogen-derived and host-endogenous molecules. Mounting evidence points towards a contribution of FPRs- via neuropathological ligands such as Amyloid beta, and neuroprotective ligands such as Humanin, Lipoxin A4, and Annexin A1- to multiple pathological aspects of neurodegenerative diseases. In this review, we aim to summarize the interplay of FPRs with neuropathological and neuroprotective ligands. Next, we depict their capability to trigger a number of ligand-dependent cell signaling pathways and their potential to interact with additional intracellular cofactors. Moreover, we highlight first studies, demonstrating that a pharmacological inhibition of FPRs helps to ameliorate neuroinflammation, which may pave the way towards novel therapeutic strategies.

Highlights

Formyl peptide receptors (FPRs) are a small family of G-protein coupled receptors that have an important role in the defense against bacterial infections (Bloes et al 2015; Dahlgren et al 2016; Migeotte et al 2006)
Formyl peptide receptors (FPRs) can trigger several receptor-dependent signal transduction pathways that play a key role in neuroinflammation and neurodegeneration
We aim to summarize the interplay of FPRs with neuropathological and neuroprotective ligands

Summary

Introduction

Formyl peptide receptors (FPRs) are a small family of G-protein coupled receptors that have an important role in the defense against bacterial infections (Bloes et al 2015; Dahlgren et al 2016; Migeotte et al 2006). Stimulation of mFpr by anti-inflammatory agonists reversed microglial reactivity and reactive oxygen species production in vitro and prevented subsequent neuronal death (Wickstead et al 2020) According to these findings, stimulation of FPRs with specific ligands may be useful to resolve neuroinflammation in the CNS, which provides an interesting but yet not tested novel treatment strategy for neurodegenerative diseases in humans. Application of Aβ1–42 induces oxidative stress and the release of pro-inflammatory markers such as Interleukin 1 β (IL-1β) in rat and murine microglia (Lorton et al 2000; Tiffany et al 2001; Wickstead 2019) These effects could be cross-desensitized by FPR agonists in rat microglia and did not occur in primary cells from mFpr2-deficient mice (Lorton et al 2000; Wickstead 2019). Table : Aβ peptides of different lengths detected in brain and cerebrospinal fluid (CSF) samples of AD patients

Brain CSF

Canonical forms

Key areas of future research