WISP1 modulates immune cell infiltration upon drug-induced liver injury (DILI)

Multiple potentially harmful stimuli challenge the liver, the chief metabolic and detoxifying organ of the body. Administration of hepatotoxic chemicals (e.g., CCl4, APAP) can induce the loss of liver mass which may lead to fatal conditions such as acute liver failure, or to chronic pathological conditions such as fibrosis, cirrhosis and hepatocellular carcinoma. Drug metabolites cause direct cell stress, trigger specific inflammatory response which removes tissue debris, followed by the regenerative response. However, an excessive inflammatory response can lead to a dramatic aggravation of the existing injury. To design interventions, which selectively target the potential detrimental effects of immune cell infiltration into damaged tissue, a detailed understanding of the pathophysiology is critical.

To unravel molecular mechanisms involved in the process of damage and regeneration, we performed gene array analyses of mouse liver tissue after single dose of CCl4 administration (1.6 g/kg body weight, i.p.) using the Affymetrix A420 2.0 gene chips. We observed an induction of a matricellular protein WISP1 during acute liver damage in mouse liver between 2h and day 1, which returned to normal levels by day 3. Genetic deletion of WISP1 caused increased liver sensitivity to damage upon CCl4 intoxication and strongly influenced the expression of inflammatory mediators such as release of cytokines and immune cell infiltration. A clear increase in macrophage and neutrophil infiltration in WISP1 KO compared to control mice was observed by immunostainings as well as a multi-color flow cytometry screen for macrophages, monocytes, neutrophils, dendritic cells, NK cells, NKT cells, T helper and cytotoxic T cells, γδ T cells and eosinophils.

In addition to the CCl4-model of acute liver damage, we currently investigate whether WISP1 influences the inflammatory response after hepatotoxic but not lethal dose of APAP injection (300 mg/kg body weight, i.p.), where WISP1 expression is induced at day 2 after APAP-induced damage. The time resolved analysis (12h, 1, 2, 3, 6, and 12 days after administration of APAP) will show the kinetics of the individual infiltrating immune cell types. Together, this will deliver comprehensive and complementary information on the spatio-termporal impact of WISP1 on liver-immune cell interactions in the context of liver damage.

In conclusion, we have strong evidence that WISP1 plays a yet unrecognized role in liver injury. Our data suggests that WISP1 is modulating the onset of inflammation and the recruitment of leukocytes (i.e. neutrophils and macrophages) upon drug-induced liver injury.

Corresponding author: Widera, Agata B

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