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J. Biol. Chem., Vol. 281, Issue 6, 3651-3659, February 10, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/6/3651    most recent M508125200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, K. Articles by Wang, J. M. Search for Related Content PubMed PubMed Citation Articles by Chen, K. Articles by Wang, J. M. Social Bookmarking                      What's this?

Activation of Toll-like Receptor 2 on Microglia Promotes Cell Uptake of Alzheimer Disease-associated Amyloid Peptide^*

Keqiang Chen, Pablo Iribarren, Jinyue Hu, Jianhong Chen, Wanghua Gong^¶, Edward H. Cho^||, Stephen Lockett^||, Nancy M. Dunlop, and Ji Ming Wang¹

From the Laboratory of Molecular Immunoregulation, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702, ^||Image Analysis Laboratory and ^¶Basic Research Program, SAIC, NCI, National Institutes of Health, Frederick, Maryland 21702, and School of Agriculture and Biology, Shanghai Jiaotong University, 201101 Shanghai, China

The human G-protein-coupled formyl peptide receptor-like 1 (FPRL1) and its mouse homologue mFPR2 mediate the chemotactic activity of a variety of polypeptides associated with inflammation and bacterial infection, including the 42-amino acid form of amyloid peptide (A₄₂), a pathogenic factor in Alzheimer disease. Because mFPR2 was inducible in mouse microglial cells by proinflammatory stimulants, such as bacterial lipopolysaccharide, a ligand for the Toll-like receptor 4 (TLR4), we investigated the role of TLR2 in the regulation of mFPR2. We found that a TLR2 agonist, peptidoglycan (PGN) derived from Gram-positive bacterium Staphylococcus aureus, induced considerable mFpr2 mRNA expression in a mouse microglial cell line and primary microglial cells. This was associated with a markedly increased chemotaxis of the cells in response to mFPR2 agonist peptides. In addition, activation of TLR2 markedly enhanced mFPR2-mediated uptake of A₄₂ by microglia. Studies of the mechanistic basis showed that PGN activates MAPK and IB, and the effect of PGN on induction of mFPR2 was dependent on signaling pathways via ERK1/2 and p38 MAPKs. The use of TLR2 on microglial cells by PGN was supported by the fact that N9 cells transfected with short interfering RNA targeting mouse TLR2 failed to show increased expression of functional mFPR2 after stimulation with PGN. Our results demonstrated a potentially important role for TLR2 in microglial cells of promoting cell responses to chemoattractants produced in lesions of inflammatory and neurodegenerative diseases in the brain.

Received for publication, July 25, 2005 , and in revised form, December 8, 2005.

^* This work was supported in part by NCI Contract NO1-CO-12400 from the National Institutes of Health. Animal care was provided in accordance with the procedures outlined in the "Guide for the Care and Use of Laboratory Animals" (National Institutes of Health Publication No. 86-23, 1985). 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 To whom correspondence should be addressed: Laboratory of Molecular Immunoregulation, Center for Cancer Research, NCI, National Institutes of Health, Bldg. 560, Rm. 31-40, Frederick, MD 21702-1201. Tel.: 301-846-6979; Fax: 301-846-7042; E-mail: wangji{at}mail.ncifcrf.gov.

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