Involvement of CCL2/CCR2 macrophage recruitment in amodiaquine-induced liver injury.

Abstract

Evidence suggests that macrophages may play a role in the development of idiosyncratic drug-induced liver injury (IDILI). However, there has yet to be a clear link between macrophage activation and the inflammatory infiltrate that is characteristic of IDILI. A major chemokine involved in the recruitment of macrophages into the liver is C-C motif chemokine ligand 2 (CCL2)/monocyte chemoattractant protein 1 (MCP1). Therefore, we tested the effect of this chemokine in an animal model of IDILI. Specifically, amodiaquine (AQ), which is known to cause IDILI in humans, causes mild liver injury in wild-type C57BL/6 mice that resolves despite continued AQ treatment, but it causes more severe liver injury that does not resolve in PD-1^-/- mice co-treated with anti-CTLA-4 to impair immune tolerance. CCR2^-/- mice treated with AQ were not protected from the expected AQ-induced liver injury seen in wild-type C57BL/6 mice. In contrast, anti-CCL2 antibodies attenuated the liver injury caused by AQ in the impaired immune tolerance model. The difference in response of the two models is likely due to a difference in the IDILI mechanism; the mild injury in wild-type animals is mediated by NK cells, while the more serious injury in the impaired immune tolerance model requires CD8 T-cells. The results from these experiments provide evidence that macrophage infiltration into the liver may not be involved in mild IDILI mediated by the innate immune system, but it does appear necessary in more severe IDILI involving cytotoxic T-cells.