Phagocytes containing a disease-promoting Toll-like receptor/Nod ligand are present in the brain during demyelinating disease in primates.
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.
Visser
Lizette
L
Department of Immunology, Erasmus Medical Center, University Medical Center Rotterdam, PO Box 2040, 3000 DR Rotterdam, The Netherlands.
Melief
Marie-José
MJ
van Riel
Debby
D
van Meurs
Marjan
M
Sick
Ella A
EA
Inamura
Seiichi
S
Bajramovic
Jeffrey J
JJ
Amor
Sandra
S
Hintzen
Rogier Q
RQ
Boven
Leonie A
LA
't Hart
Bert A
BA
Laman
Jon D
JD
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D002144:Callithrix / Q000276:immunology*; D003711:Demyelinating Diseases / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental; D005260:Female; D006801:Humans; D007249:Inflammation; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008024:Ligands; D008253:Macaca mulatta / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009113:Muramidase / Q000378:metabolism; D009238:N-Acetylmuramoyl-L-alanine Amidase / Q000378:metabolism; D010457:Peptidoglycan / Q000276:immunology; D010586:Phagocytes / Q000276:immunology / Q000378:metabolism*; D012995:Solubility; D013211:Staphylococcus aureus; D051193:Toll-Like Receptors / Q000378:metabolism*
D008024:Ligands; D010457:Peptidoglycan; D051193:Toll-Like Receptors; D009113:Muramidase; D009238:N-Acetylmuramoyl-L-alanine Amidase