B cell-derived acetylcholine promotes liver regeneration by regulating Kupffer cell and hepatic CD8+ T cell function
Nastaran Fazel Modares, Liam D. Hendrikse, Logan K. Smith, Michael St. Paul, Jillian Haight, Ping Luo, Shaofeng Liu, Jérôme Fortin, Frances Tong, Andrew Wakeham, Soode Moghadas Jafari, Chunxing Zheng, Mackenzie Buckland, Robert Flick, Jennifer Silvester, Thorsten Berger, Troy Ketela, Simone Helke, Erica Foffi, Raheleh Niavarani, Ryan Mcwilliam, Mary Saunders, Isabelle Colonna, Bruna Araújo David, Tashi Rastogi, Woo‐Yong Lee, Paul Kubes, Tak W. Mak
Abstract
<h2>Summary</h2> Liver regeneration (LR) is essential for recovery from acute trauma, cancer surgery, or transplantation. Neurotransmitters such as acetylcholine (ACh) play a role in LR by stimulating immune cells and augmenting hepatocyte proliferation, but the source of this ACh remains unclear. Here, we demonstrated that B cells expressing choline acetyltransferase (ChAT), which synthesizes ACh, were required for LR. Mice lacking ChAT<sup>+</sup> B cells subjected to partial hepatectomy (PHX) displayed greater mortality due to failed LR. Kupffer cells and hepatic CD8<sup>+</sup> T cells expressed the α7 nicotinic ACh receptor (nAChR), and LR was disrupted in mice lacking α7 nAChR. Mechanistically, B cell-derived ACh signaled through α7 nAChR to positively regulate the function of regenerative Kupffer cells and to control the activation of hepatic CD8<sup>+</sup> T cells to curtail harmful interferon-gamma (IFNγ) production. Our work offers insights into LR mechanisms that may point to therapies for liver damage.