538 Bacterial Receptor NOD1 Regulates in the Neutrophil Migration Machinery During Liver Injury

Abstract

assessed. Results: TLR9±TLR2 priming of IRF7and IFNAR1/2-deficient mice resulted in significantly lower induction of IFNβ and interferon stimulated gene 15 (ISG15) expression compared to WT mice. In contrast, IRF7and IFNAR1/2-deficient mice showed a significant increase in the number of granulomas and serum ALT levels indicating liver damage after TLR9±2 priming compared to WT mice. As this finding suggested a protective role for typeI IFNs in liver injury, we analyzed the expression of pro-and anti-inflammatory genes that contribute to liver injury. Interleukin-1 receptor antagonist (IL-1ra) is an interferon-regulated anti-inflammatory cytokine that acts as an antagonist of the pro-inflammatory cytokine, IL1. We found that IRF7-and IFNRA1/2-deficient mice had a significant decrease in liver IL1ra expression but an increase in IL-1β/IL1ra ratio compared to WT suggesting a preferential pro-inflammatory activation. To further assess mechanisms for the increased inflammatory cell infiltrates in the IRF7and IFNRA1/2-deficient mice, we evaluated the ratio of immature andmature dendritic cells (DC) in the livers.We found increased expression of the chemokine receptor 1 (CCR1), a marker of immature DC, and decreased expression of CCR7, a marker of mature DCs, both in IRF7and IFNAR1/2-deficient mice after TLR9±TLR2 priming compared to WT mice suggesting immature DC recruitment in the absence of type I IFN signaling. Conclusions: Our results support the hypothesis that type I IFN induction via IRF7 has hepatoprotective and anti-inflammatory effects in TLR9-induced liver damage. Disruption of type I IFN induction (IRF7 deficiency) or signaling (IFNRA1/2 deficiency) increases liver injury due to dysregulation of IL-1ra expression and predominant immature DC recruitment. Type I IFNs may have protective effects in other forms of liver diseases. (Supported by DK075635)