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Induction of the Formyl Peptide Receptor 2 in Microglia by IFN- and Synergy with CD40 Ligand^1,2

Keqiang Chen^*,, Pablo Iribarren^*, Jian Huang^*, Lingzhi Zhang^¶, Wanghua Gong, Edward H. Cho, Stephen Lockett, Nancy M. Dunlop^* and Ji Ming Wang^3,*

^* Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702; Image Analysis Laboratory and Basic Research Program, Science Applications International Corporation, National Cancer Institute at Frederick, Frederick, MD 21702; School of Agriculture and Biology, Shanghai Jiaotong University, Shanghai, China; and ^¶ Shanghai Asia United Antibody Medical, Shanghai, China

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 1–42 (A₄₂), 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- and the CD40 ligand (CD40L) to affect the expression and function of mFPR2. We found that IFN-, 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 A₄₂. IFN- also increased the endocytosis of A₄₂ by microglial cells via mFPR2. The effect of IFN- on mFPR2 expression in microglial cells was dependent on activation of MAPK and IB-. IFN- additionally increased the expression of CD40 by microglial cells and soluble CD40L significantly promoted cell responses to IFN- during a 6-h incubation period by enhancing the activation of MAPK and IB- signaling pathways. We additionally found that the effect of IFN- and its synergy with CD40L on mFPR2 expression in microglia was mediated in part by TNF-. Our results suggest that IFN- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. NO1-CO-12400. The research was also supported (in part) by the Intramural Research Program of the National Cancer Institute, National Institutes of Health.

² The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NCI-Frederick is accredited by the American Association for the Accreditation of Laboratory Animal Care International and follows the Public Health Service Policy for the Care and Use of Laboratory Animals. Animal care was provided in accordance with the procedures outlined in the "Guide for Care and Use of Laboratory Animals" (National Research Council; 1996; National Academy Press, Washington D.C.).

³ Address correspondence and reprint requests to Dr. Ji Ming Wang, Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute at Frederick, Building 560, Room 31-76, Frederick, MD 21702-1201. E-mail address: wangji{at}mail.ncifcrf.gov

⁴ Abbreviations used in this paper: AD, Alzheimer’s disease; A, amyloid ; BBB, blood-brain barrier; CD40L, CD40 ligand; CI, chemotaxis index; FI, fluorescence intensity; fMLF, formyl-methionyl-leucyl-phenylalanine; mFPR2, mouse formyl peptide receptor 2; PI, propidium iodide; PTX, pertussis toxin; BBB, blood-brain barrier.

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