Vagus-macrophage-hepatocyte link promotes post-injury liver regeneration and whole-body survival through hepatic FoxM1 activation

Tomohito Izumi, Junta Imai (), Junpei Yamamoto, Yohei Kawana, Akira Endo, Hiroto Sugawara, Masato Kohata, Yoichiro Asai, Kei Takahashi, Shinjiro Kodama, Keizo Kaneko, Junhong Gao, Kenji Uno, Shojiro Sawada, Vladimir V. Kalinichenko, Yasushi Ishigaki, Tetsuya Yamada and Hideki Katagiri
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Tomohito Izumi: Tohoku University Graduate School of Medicine
Junta Imai: Tohoku University Graduate School of Medicine
Junpei Yamamoto: Tohoku University Graduate School of Medicine
Yohei Kawana: Tohoku University Graduate School of Medicine
Akira Endo: Tohoku University Graduate School of Medicine
Hiroto Sugawara: Tohoku University Graduate School of Medicine
Masato Kohata: Tohoku University Graduate School of Medicine
Yoichiro Asai: Tohoku University Graduate School of Medicine
Kei Takahashi: Tohoku University Graduate School of Medicine
Shinjiro Kodama: Tohoku University Graduate School of Medicine
Keizo Kaneko: Tohoku University Graduate School of Medicine
Junhong Gao: Tohoku University Graduate School of Medicine
Kenji Uno: Tohoku University Graduate School of Medicine
Shojiro Sawada: Tohoku University Graduate School of Medicine
Vladimir V. Kalinichenko: Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center
Yasushi Ishigaki: Tohoku University Graduate School of Medicine
Tetsuya Yamada: Tohoku University Graduate School of Medicine
Hideki Katagiri: Tohoku University Graduate School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract The liver possesses a high regenerative capacity. Liver regeneration is a compensatory response overcoming disturbances of whole-body homeostasis provoked by organ defects. Here we show that a vagus-macrophage-hepatocyte link regulates acute liver regeneration after liver injury and that this system is critical for promoting survival. Hepatic Foxm1 is rapidly upregulated after partial hepatectomy (PHx). Hepatic branch vagotomy (HV) suppresses this upregulation and hepatocyte proliferation, thereby increasing mortality. In addition, hepatic FoxM1 supplementation in vagotomized mice reverses the suppression of liver regeneration and blocks the increase in post-PHx mortality. Hepatic macrophage depletion suppresses both post-PHx Foxm1 upregulation and remnant liver regeneration, and increases mortality. Hepatic Il-6 rises rapidly after PHx and this is suppressed by HV, muscarinic blockade or resident macrophage depletion. Furthermore, IL-6 neutralization suppresses post-PHx Foxm1 upregulation and remnant liver regeneration. Collectively, vagal signal-mediated IL-6 production in hepatic macrophages upregulates hepatocyte FoxM1, leading to liver regeneration and assures survival.

Date: 2018
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DOI: 10.1038/s41467-018-07747-0

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