Induction of the formyl peptide receptor 2 in microglia by IFN-gamma and synergy with CD40 ligand

• Published in: Journal of Immunology 2007-02, Vol.178 (3), p.1759-1766
• Main Authors: Chen, Keqiang, Iribarren, Pablo, Huang, Jian, Zhang, Lingzhi, Gong, Wanghua, Cho, Edward H, Lockett, Stephen, Dunlop, Nancy M, Wang, Ji Ming
• Format: Article
• Language: English
• Subjects: Animals; CD40 Ligand - pharmacology; Cell Movement - drug effects; Drug Synergism; Gene Expression Regulation - drug effects; Interferon-gamma - pharmacology; Mice; Microglia - cytology; Microglia - metabolism; Receptors, Formyl Peptide - genetics; RNA, Messenger - drug effects; Signal Transduction; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.178.3.1759

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 beta 1-42 (Abeta(42)), 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-gamma and the CD40 ligand (CD40L) to affect the expression and function of mFPR2. We found that IFN-gamma, 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 Abeta(42). IFN-gamma also increased the endocytosis of Abeta(42) by microglial cells via mFPR2. The effect of IFN-gamma on mFPR2 expression in microglial cells was dependent on activation of MAPK and IkappaB-alpha. IFN-gamma additionally increased the expression of CD40 by microglial cells and soluble CD40L significantly promoted cell responses to IFN-gamma during a 6-h incubation period by enhancing the activation of MAPK and IkappaB-alpha signaling pathways. We additionally found that the effect of IFN-gamma and its synergy with CD40L on mFPR2 expression in microglia was mediated in part by TNF-alpha. Our results suggest that IFN-gamma 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.