Critical role of toll-like receptors and the common TLR adaptor, MyD88, in induction of granulomas and liver injury.
OBJECTIVE
Toll-like receptors (TLR) recognize pathogens and regulate innate immune activation. Here, we investigated the roles of TLR9 and the common TLR adaptor, MyD88, in liver injury.


METHODS
C57BL6, TLR9(-/-), IFNgamma(-/-) or MyD88(-/-) mice were primed with Propionibacterium acnes, TLR9 (CpG) or TLR2 (lipoteichoic acid) ligands followed by LPS challenge. ALT, cytokines and liver histology were assessed.


RESULTS
Selective priming through TLR9 but not TLR2 induced granulomas, elevated serum ALT, and sensitized C57BL6 mice to increased LPS-induced serum IL-6, IL-12 and IFNgamma levels. Further, TLR2 and TLR9 ligands synergized in induction of granulomas and sensitization to LPS-induced inflammation. IFNgamma induction by P. acnes, TLR2 and TLR9 ligands required MyD88. In MyD88(-/-) mice P. acnes failed to induce granulomas and both MyD88 and TLR9 deficiency prevented P. acnes-induced sensitization to LPS. Increased mRNA expression of genes of the TLR4 signaling complex (TLR4, CD14, MD-2, and MyD88) and the NADPH complexes (p47phox, p67phox, gp91phox, and p22phox) was induced by priming with P. acnes or TLR9 plus TLR2 suggesting mechanisms for LPS sensitization and liver injury.


CONCLUSIONS
TLR9+/-TLR2 activation via MyD88-dependent pathways plays a pivotal role in liver sensitization and granuloma formation.
Velayudham
Arumugam
A
Liver Center, Department of Medicine, University of Massachusetts Medical School, Plantation Street, Worcester, MA 01605, USA.
Hritz
Istvan
I
Dolganiuc
Angela
A
Mandrekar
Pranoti
P
Kurt-Jones
Evelyn
E
Szabo
Gyongyi
G
D033942:Adaptor Proteins, Vesicular Transport / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D015870:Gene Expression; D006099:Granuloma / Q000209:etiology* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D008107:Liver Diseases / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D007371:Interferon-gamma; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D051193:Toll-Like Receptors; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse