Use of TLR9 and TLR7/8 agonists in combination with d-galactosamine in exploring models for distinct severities of systemic inflammation relative to liver injury.

Challenges with various TLR ligands (TLRLs)in combination with D-galactosamine (GalN) in rodents may mimic diverse conditions of acute inflammation and organ failure. Here, we report that CpG (ODN1826, TLR9 agonist)/GalN induced a liver-specific injury with modest systemic effects, whereas R848 (resiquimod, TLR7/8 agonist)/GalN exhibited systemic and liver toxicity. We also observed the protective effect of Gr-1+ cells (the population containing neutrophils) against liver injury in both the R848/GalN and CpG/GalN models. In cytokine measurements, the intraperitoneal administration of antibodies showed a non-specific tolerance induction effect, which was more pronounced in the CpG/GalN than in the R848/GalN model. Cytokine analyses also suggested that the TLR9 agonist/GalN induced a limited degree of systemic inflammation compared to TLR7/8 agonist/GalN models. The relevance of this finding to the TLR9-mediated induction of stress tolerance (protective effect) in non-immune cells is discussed.