Phagocytes containing a disease-promoting Toll-like receptor/Nod ligand are present in the brain during demyelinating disease in primates

Lizette Visser, Marie-José Melief, Debby van Riel, Marjan van Meurs, Ella A Sick, Seiichi Inamura, Jeffrey J Bajramovic, Sandra Amor, Rogier Q Hintzen, Leonie A Boven, Bert A 't Hart, Jon D Laman

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Recent studies claim a central role for Toll-like receptor (TLR) ligands in stimulating autoimmune disease by activation of antigen-presenting cells in the target organ, but it is unclear if and how TLR ligands reach target organs. Most evidence comes from rodent models, and it is uncertain whether this principle holds in primates. Here we identify which cells contain peptidoglycan (PGN) in multiple sclerosis brain and in two nonhuman primate experimental autoimmune encephalomyelitis (EAE) models with different disease courses: acute (rhesus monkey) versus chronic disease (marmoset). Because persistence of TLR ligands in the central nervous system might be consequential for disease progression, we also determined the expression of two major PGN-degrading enzymes, ie, lysozyme and N-acetylmuramyl-l-alanine amidase. Distinct phagocyte subsets, including granulocytes, macrophages, and dendritic cells, contained PGN in the brain and coexpressed the inflammatory cytokine interleukin-12. The number of phagocytes carrying PGN increased in acute and chronic EAE compared with control animals, with the highest number of PGN-containing cells in acute EAE brain. Lytic enzymes were scarcely expressed in monkey and multiple sclerosis brain, favoring PGN persistence. PGN stimulated interleukin-12p70 release by leukocytes from all three primate species. The presence of PGN in the inflamed brain may have major implications because TLR2/Nod ligation potentially promotes inflammation and disease progression.

Original languageEnglish
Pages (from-to)1671-85
Number of pages15
JournalThe American Journal of Pathology
Issue number5
Publication statusPublished - Nov 2006


  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Brain
  • Callithrix
  • Demyelinating Diseases
  • Encephalomyelitis, Autoimmune, Experimental
  • Female
  • Humans
  • Inflammation
  • Journal Article
  • Leukocytes, Mononuclear
  • Ligands
  • Macaca mulatta
  • Male
  • Middle Aged
  • Muramidase
  • N-Acetylmuramoyl-L-alanine Amidase
  • Peptidoglycan
  • Phagocytes
  • Research Support, Non-U.S. Gov't
  • Solubility
  • Staphylococcus aureus
  • Toll-Like Receptors

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