Involvement of formyl peptide receptors in receptor for advanced glycation end products (RAGE) - and amyloid beta 1-42-induced signal transduction in glial cells

Abstract

BackgroundRecent studies suggest that the chemotactic G-protein-coupled-receptor (GPCR) formyl-peptide-receptor-like-1 (FPRL1) and the receptor-for-advanced-glycation-end-products (RAGE) play an important role in the inflammatory response involved in neurodegenerative disorders such as Alzheimer’s disease (AD).Therefore, the expression and co-localisation of mouse formyl peptide receptor (mFPR) 1 and 2 as well as RAGE in an APP/PS1 transgenic mouse model using immunofluorescence and real-time RT-PCR were analysed. The involvement of rat or human FPR1/FPRL1 (corresponds to mFPR1/2) and RAGE in amyloid-β 1–42 (Aβ1-42)-induced signalling were investigated by extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation. Furthermore, the cAMP level in primary rat glial cells (microglia and astrocytes) and transfected HEK 293 cells was measured. Formyl peptide receptors and RAGE were inhibited by a small synthetic antagonist WRW4 and an inactive receptor variant delta-RAGE, lacking the intracytoplasmatic domains.ResultsWe demonstrated a strong increase of mFPR1/2 and RAGE expression in the cortex and hippocampus of APP/PS1 transgenic mice co-localised to the glial cells. In addition, the Aβ1-42-induced signal transduction is dependant on FPRL1, but also on FPR1. For the first time, we have shown a functional interaction between FPRL1/FPR1 and RAGE in RAGE ligands S100B- or AGE-mediated signalling by ERK1/2 phosphorylation and cAMP level measurement. In addition a possible physical interaction between FPRL1 as well as FPR1 and RAGE was shown with co-immunoprecipitation and fluorescence microscopy.ConclusionsThe results suggest that both formyl peptide receptors play an essential role in Aβ1-42-induced signal transduction in glial cells. The interaction with RAGE could explain the broad ligand spectrum of formyl peptide receptors and their important role for inflammation and the host defence against infections.

Lack of formyl peptide receptor 1 and 2 leads to more severe inflammation and higher mortality in mice with of pneumococcal meningitis

“…Our own previous investigations revealed a vivid expression of mFPR2 in the mouse brain whereas the mFPR1 is endogenously only weakly detectable. 22 However, the results of our mortality study revealed a significant decrease in survival after pneumococcal meningitis for both mFPR1-and mFPR2-deficient mice but there were no difference between mFPR1 and mFPR2. These results are supported by another study using infection models: Gao et al 16 reported an increased susceptibility to Listeria monocytogenes for mFPR1-deficient mice as measured by increased mortality and bacterial load in spleen and liver compared with wild-type littermates.…”

“…37 Interestingly, the chemotactic G-protein-coupled FPRs interact with a menagerie of structurally diverse pro-inflammatory and anti-inflammatory ligands associated with different diseases, including amyloidosis, Alzheimer's disease, prion disease and HIV. 22,38,39 We compared the effect of mFPR1 or mFPR2 deficiency after pneumococcal meningitis. Sequence comparison of both receptors revealed a similarity of 63%.…”

Expression and Function of Psoriasin (S100A7) and Koebnerisin (S100A15) in the Brain

“…The transfection and selection of HEK293 cells expressing FPRL1, hRAGE, or ⌬RAGE were described previously (37,38). The pcDNA3.1-RAGE plasmid containing a neomycin resistance gene was kindly provided by R. Donato (Perugia, Italy) (39).…”

DNAX-activating Protein 10 (DAP10) Membrane Adaptor Associates with Receptor for Advanced Glycation End Products (RAGE) and Modulates the RAGE-triggered Signaling Pathway in Human Keratinocytes

“…Moreover, Slowik et al (25) showed that formyl peptide receptors, to which amyloid-␤ can bind, interact with RAGE and augment the enhanced signal transduction of ERK1/2 in HEK293 cells. However, Emmprin and TLR2/4 do not directly interact with RAGE.…”