Cooperation between NOD2 and Toll-like receptor 2 ligands in the up-regulation of mouse mFPR2, a G-protein-coupled Abeta42 peptide receptor, in microglial cells.
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 beta(42), 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-kappaB 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.
Chen
Keqiang
K
School of Agriculture and Biology, Shanghai Jiaotong University, Shanghai, China.
Zhang
Lingzhi
L
Huang
Jian
J
Gong
Wanghua
W
Dunlop
Nancy M
NM
Wang
Ji Ming
JM
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005786:Gene Expression Regulation; D020672:I-kappa B Proteins / Q000502:physiology; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D053473:Nod2 Signaling Adaptor Protein / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D044042:Receptors, Formyl Peptide / Q000235:genetics*; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D015854:Up-Regulation
D020672:I-kappa B Proteins; D008024:Ligands; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D012333:RNA, Messenger; D044042:Receptors, Formyl Peptide; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C481578:formyl peptide receptor 2, mouse; D000072000:NF-KappaB Inhibitor alpha; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D048049:Extracellular Signal-Regulated MAP Kinases