Exacerbated Immune Complex-Mediated Vascular Injury in Mice with Heterozygous Deficiency of Aryl Hydrocarbon Receptor through Upregulation of Fcγ Receptor III Expression on Macrophages.

Abstract

Aryl hydrocarbon receptor (AhR), which was discovered as a receptor for environmental concomitants, plays an important role widely in the immune system. In this study, we assessed AhR involvement in immune-complex-mediated vascular injury by examining the reverse-passive Arthus reaction in AhR heterozygous knockout (AhR+/-) mice. In the cutaneous Arthus reaction, dermal edema was severer in AhR+/- mice than in wild-type mice. The number of infiltrating neutrophils and mRNA expression levels of CXC chemokine ligand 1 and IL-6 were also increased in AhR+/- mice. Similarly, in the peritoneal Arthus reaction, infiltration of neutrophils was increased in AhR+/- mice. Peritoneal macrophages from AhR+/- mice expressed higher levels of Fcγ receptor III and produced higher levels of CXC chemokine ligand 1 and IL-6 after immune complex treatment. In addition, AhR occupied the promoter regions of Fcγ receptor III gene in peritoneal macrophages in a ligand-dependent manner. Depletion of macrophages reduced the cutaneous Arthus reaction in AhR+/- mice, and adoptive transfer of AhR+/- mice macrophages into wild-type mice exacerbated the peritoneal Arthus reaction. Furthermore, AhR expression was decreased and Fcγ receptor III expression was increased in CD14+ monocytes in peripheral blood from patients with immune-complex-mediated vasculitis compared with those from healthy controls. These results suggest that downregulation of AhR is associated with the exacerbation of immune-complex-mediated vascular injury.