Published online before print February 25, 2008

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(Journal of Leukocyte Biology. 2008;83:1467-1475.)
© 2008 by Society for Leukocyte Biology

Cooperation between NOD2 and Toll-like receptor 2 ligands in the up-regulation of mouse mFPR2, a G-protein-coupled Aβ₄₂ peptide receptor, in microglial cells

Keqiang Chen^*,, Lingzhi Zhang, Jian Huang, Wanghua Gong, Nancy M. Dunlop and Ji Ming Wang^,1

^* School of Agriculture and Biology, Shanghai Jiaotong University, Shanghai, China;
Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, and
Basic Research Program, SAIC-Frederick, National Cancer Institute-Frederick, Frederick, Maryland, USA

¹Correspondence: Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Building 560, Room 31-76, Frederick, MD 21702-1201, USA. E-mail: wangji{at}mail.ncifcrf.gov

Human G-protein-coupled formyl peptide receptor-like 1 and its mouse homologue formyl peptide receptor 2 (mFPR2) mediate the chemotactic activity of a variety of pathogen and host-derived peptides, including amyloid β₄₂, a key causative factor in Alzheimer’s disease. In mouse microglia, mFPR2 is up-regulated by pathogen-associated molecular patterns and proinflammatory cytokines, as shown, for instance, in our previous study using peptidoglycan (PGN) of Gram⁺ bacteria. As PGN and its components have been reported to use TLR2 and an intracellular receptor nucleotide-binding oligomerization domain 2 (NOD2), we investigated the capacity of palmitoyl-cys[(RS)-2, 3-di(palmitoyloxy)-propyl]-Ala-Gly-OH (PamCAG), a specific TLR2 ligand, and muramyl dipeptide (MDP), a NOD2 ligand, to cooperatively regulate the expression and function of mFPR2 in microglia. We found that MDP and PamCAG as well as another TLR2-specific agonist palmitoyl-3-cysteine-serine-lysine-4 (Pam3CSK4), when used alone, each increased the expression of functional mFPR2 in microglial cells, and the combination of MDP and PamCAG or Pam3CSK4 exhibited an additive effect. Mechanistic studies revealed that MDP increased the levels of TLR2 expression on the microglial cell surface and enhanced the levels of MAPKs p-38, ERK1/2, and NF-B activated by PamCAG. Our results suggest that TLR2 and NOD2 cooperate to up-regulate the expression of mFPR2 and therefore, may actively participate in the pathogenic processes of brain inflammation and neurodegenerative diseases.

Key Words: TLR2 • chemotaxis