Toll-like receptor 2 mediates inflammatory cytokine induction but not sensitization for liver injury byPropioni- bacterium acnes

Abstract Recognition of Gram-positive bacteria by Toll-like receptor 2 (TLR2) induces activation of proinflammatory pathways. In mice, sensitization with the Gram-positive Propionibacterium acnes followed by a challenge with the TLR4 ligand, lipopolysaccharide (LPS), results in fulminant hepatic failure. Here, we investigated the role of TLR2 in liver sensitization to LPS-induced injury. Stimulation of Chinese hamster ovary cells and peritoneal macrophages with heat-killed P. acnes required expression of TLR2 but not of TLR4, suggesting that P. acnes was a TLR2 ligand. Cell activation by P. acnes was myeloid differentiation primary-response protein 88 (MyD88)-dependent, and it was augmented by coexpression of CD14 in mouse peritoneal macrophages. In vitro, P. acnes behaved as a TLR2 ligand and induced TLR4 hetero- and TLR2 homotolerance in peritoneal macrophages. In vivo priming of wild-type mice with P. acnes, but not with the selective TLR2 ligands peptidoglycan and lipotheicoic acid, resulted in hepatocyte necrosis, hyperelevated serum levels of tumor necrosis factor α (TNF-α), interleukin (IL)-6, interferon-γ (IFN-γ), and IL-12 (p40/p70), and increased RNA expression of proinflammatory cytokines (IL-12p40, IL-1α, IL-6, IL-1β, IL-18, IFN-γ) in the liver after a LPS challenge. Furthermore, P. acnes priming sensitized TLR2-deficient (TLR2−/−) but not MyD88−/− mice to LPS-induced injury, evidenced by hepatocyte necrosis, increased levels of serum TNF-α, IFN-γ, IL-6, and liver proinflammatory cytokine mRNA expression. IFN-γ, a cytokine sensitizing to endotoxin, was induced by P. acnes in splenocytes of TLR2−/− and TLR9−/− but not MyD88−/− mice. These results suggest that although P. acnes triggers TLR2-mediated cell activation, TLR2-independent but MyD88-dependent mechanisms mediate in vivo sensitization by P. acnes for LPS-induced liver injury.