Inhibition of aquaporin-3 in macrophages by a monoclonal antibody as potential therapy for liver injury

• Published in: Nature communications Vol. 11; no. 1; pp. 5666 - 14
• Main Authors: Hara-Chikuma, Mariko, Tanaka, Manami, Verkman, Alan S., Yasui, Masato
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.11.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 38/89; 631/154; 64/60; 692/4017; 692/4020/4021/1607; 82/1; 96/106; 96/109; 96/31; Animal models; Aquaporin 3; Aquaporins; Carbon tetrachloride; CCL4 protein; Cell activation; Epithelial cells; Epitopes; Fibrosis; Glycerol; Hepatocytes; Humanities and Social Sciences; Hydrogen peroxide; Injury prevention; Liver; Macrophages; Monoclonal antibodies; multidisciplinary; NF-κB protein; Oxidative stress; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19491-5

Aquaporin 3 (AQP3) is a transporter of water, glycerol and hydrogen peroxide (H 2 O 2 ) that is expressed in various epithelial cells and in macrophages. Here, we developed an anti-AQP3 monoclonal antibody (mAb) that inhibited AQP3-facilitated H 2 O 2 and glycerol transport, and prevented liver injury in experimental animal models. Using AQP3 knockout mice in a model of liver injury and fibrosis produced by CCl 4 , we obtained evidence for involvement of AQP3 expression in nuclear factor-κB (NF-κB) cell signaling, hepatic oxidative stress and inflammation in macrophages during liver injury. The activated macrophages caused stellate cell activation, leading to liver injury, by a mechanism involving AQP3-mediated H 2 O 2 transport. Administration of an anti-AQP3 mAb, which targeted an extracellular epitope on AQP3, prevented liver injury by inhibition of AQP3-mediated H 2 O 2 transport and macrophage activation. These findings implicate the involvement of macrophage AQP3 in liver injury, and provide evidence for mAb inhibition of AQP3-mediated H 2 O 2 transport as therapy for macrophage-dependent liver injury. Aquaporin 3 (AQP3) is a transporter of water, glycerol and hydrogen peroxide, and hydrogen peroxide mediated oxidative stress has been implicated in liver injury. Here, the authors report the development of an anti-AQP3 monoclonal antibody, which alleviates liver injury in multiple mouse models.