TY - JOUR
T1 - Inhibition of aquaporin-3 in macrophages by a monoclonal antibody as potential therapy for liver injury
AU - Hara-Chikuma, Mariko
AU - Tanaka, Manami
AU - Verkman, Alan S.
AU - Yasui, Masato
N1 - Funding Information:
We thank Drs. Hiroki Satooka, Sachiko Watanabe, and Catharina Sagita Moniaga for supporting preliminary experiments. We thank Drs. Shu Narumiya, Noriyuki Morikawa, and Yoshiaki Morita, and Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University for supporting development of anti-AQP3 antibody. We thank Drs. Maruyama and Okumura for supporting the experiment using AQP3 peptide mutants. We thank Dr. Hayato Takahashi for providing CD45.1 mice. We thank Dr. Kazuo Umezawa for providing DHMEQ reagent. This work was supported in part by grants from Astellas Pharma Inc. in the Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program (M.H.-C.), the Princess Takamatsu Cancer Research Fund (15-24717, M.H.-C.), Keio University Academic Development Funds (M.H.-C.), Suntory Global Innovation Center Ltd.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12
Y1 - 2020/12
N2 - Aquaporin 3 (AQP3) is a transporter of water, glycerol and hydrogen peroxide (H2O2) that is expressed in various epithelial cells and in macrophages. Here, we developed an anti-AQP3 monoclonal antibody (mAb) that inhibited AQP3-facilitated H2O2 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 CCl4, 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 H2O2 transport. Administration of an anti-AQP3 mAb, which targeted an extracellular epitope on AQP3, prevented liver injury by inhibition of AQP3-mediated H2O2 transport and macrophage activation. These findings implicate the involvement of macrophage AQP3 in liver injury, and provide evidence for mAb inhibition of AQP3-mediated H2O2 transport as therapy for macrophage-dependent liver injury.
AB - Aquaporin 3 (AQP3) is a transporter of water, glycerol and hydrogen peroxide (H2O2) that is expressed in various epithelial cells and in macrophages. Here, we developed an anti-AQP3 monoclonal antibody (mAb) that inhibited AQP3-facilitated H2O2 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 CCl4, 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 H2O2 transport. Administration of an anti-AQP3 mAb, which targeted an extracellular epitope on AQP3, prevented liver injury by inhibition of AQP3-mediated H2O2 transport and macrophage activation. These findings implicate the involvement of macrophage AQP3 in liver injury, and provide evidence for mAb inhibition of AQP3-mediated H2O2 transport as therapy for macrophage-dependent liver injury.
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U2 - 10.1038/s41467-020-19491-5
DO - 10.1038/s41467-020-19491-5
M3 - Article
C2 - 33168815
AN - SCOPUS:85095702290
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5666
ER -