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Induction of the Formyl Peptide Receptor 2 in Microglia by IFN-γ and Synergy with CD40 Ligand12

Human formyl peptide receptor (FPR)-like 1 (FPRL1) and its mouse homologue mFPR2 are functional receptors for a variety of exogenous and host-derived chemotactic peptides, including amyloid β 1–42 (Aβ42), a pathogenic factor in Alzheimer’s disease. Because mFPR2 in microglial cells is regulated by proinflammatory stimulants including TLR agonists, in this study we investigated the capacity of IFN-γ and the CD40 ligand (CD40L) to affect the expression and function of mFPR2. We found that IFN-γ, when used alone, induced mFPR2 mRNA expression in a mouse microglial cell line and primary microglial cells in association with increased cell migration in response to mFPR2 agonists, including Aβ42. IFN-γ also increased the endocytosis of Aβ42 by microglial cells via mFPR2. The effect of IFN-γ on mFPR2 expression in microglial cells was dependent on activation of MAPK and IκB-α. IFN-γ additionally increased the expression of CD40 by microglial cells and soluble CD40L significantly promoted cell responses to IFN-γ during a 6-h incubation period by enhancing the activation of MAPK and IκB-α signaling pathways. We additionally found that the effect of IFN-γ and its synergy with CD40L on mFPR2 expression in microglia was mediated in part by TNF-α. Our results suggest that IFN-γ and CD40L, two host-derived factors with increased concentrations in inflammatory central nervous system diseases, may profoundly affect microglial cell responses in the pathogenic process in which mFPR2 agonist peptides are elevated.