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.

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“…Activation of AHR (Fig. 2b), the aryl hydrocarbon receptor, is also associated with promoting vascular inflammation; however, downregulation of AHR can also exacerbate vascular injury by enhancing the function of monocytes and macrophages (Wu et al 2011;Nakajima et al 2018). Statins, widely known for their ability to decrease cholesterol and reduce atherosclerosis via the inhibition of HMGCR (Fig.…”