Activation of the pro-resolving receptors Fpr2/3 attenuate lipopolysaccharide-induced inflammatory microglial activation

Neuroinflammation driven primarily by microglia directly contributes to neuronal death in many neurodegenerative diseases. Classical anti-inflammatory approaches aim to suppress pro-inflammatory mediator production, but exploitation of inflammatory resolution, the active endogenous process whereby inflammation is terminated, may also be of benefit. A key driver of peripheral inflammatory resolution, formyl peptide receptors 2/3 (Fpr2/3), is expressed by microglia, but its therapeutic potential in neurodegeneration remains unclear. Here, we sought to provide a proof-of-principle that Fpr2/3 targeting could reverse inflammatory microglial activation induced by the potent bacterial inflammogen lipopolysaccharide (LPS). Stimulation of murine BV2 microglia with LPS triggered release of nitric oxide, TNFα and IL-10, upregulated surface expression of CD38 and CD40 and suppressed CD206, all of which were reduced by subsequent treatment with the Fpr2/3 ligand C43. Cellular exposure to LPS also stimulated NADPH oxidase and mitochondrial derived reactive oxygen species production, effects reversed by C43 treatment. Mechanistic studies showed C43 to act through p38 MAPK phosphorylation and reduction of LPS-induced NFκB nuclear translocation through prevention of IκBα degradation. Here, we provide proof-of-concept data indicating exploitation of the pro-resolving receptor Fpr2/3 as a promising therapeutic strategy in neuroinflammatory conditions.Competing Interest StatementThe authors have declared no competing interest.List of abbreviationsFPR2Human formyl peptide receptor 2Fpr2/3Murine formyl peptide receptors 2/3IL-10Interleukin 10LPSLipopolysaccharideROSReactive oxygen speciesTNFαTumour necrosis factor alphaWRW4Trp-Arg-Trp-Trp-Trp-TrpView Full Text