Induction of the formyl peptide receptor 2 in microglia by IFN-gamma and synergy with CD40 ligand.
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.
Chen
Keqiang
K
Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
Iribarren
Pablo
P
Huang
Jian
J
Zhang
Lingzhi
L
Gong
Wanghua
W
Cho
Edward H
EH
Lockett
Stephen
S
Dunlop
Nancy M
NM
Wang
Ji Ming
JM
D000818:Animals; D023201:CD40 Ligand / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects*; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects; D044042:Receptors, Formyl Peptide / Q000235:genetics*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D012333:RNA, Messenger; D044042:Receptors, Formyl Peptide; D014409:Tumor Necrosis Factor-alpha; C481578:formyl peptide receptor 2, mouse; D023201:CD40 Ligand; D007371:Interferon-gamma