Acetylcholine derived from B lymphocytes controls liver regeneration
Humans recover from hepatic injury largely by liver regeneration. This complicated process requires hepatocyte proliferation driven by collaboration amongst multiple hepatic cell types. Immune cells also contribute, with some producing mitogenic cytokines such as IL-6 but others damaging hepatocytes by secreting IFN?. A better understanding of immune cell functions in liver regeneration is necessary to improve clinical interventions. Here, we demonstrate that B cells expressing choline acetyltransferase (ChAT), the enzyme synthesizing acetylcholine (ACh), are specifically required for liver regeneration.  Mice lacking ChAT+ B cells subjected to partial hepatectomy (PHX) display greater mortality due to failed liver regeneration. We show that both Kupffer cells and hepatic CD8+ T cells express the a7 nicotinic ACh receptor (nAChR; encoded by Chrna7), and that liver regeneration is also disrupted in mice lacking a7 nAChR. Thus, two regulatory axes promoting hepatocyte proliferation operate following PHX: one where hepatic ChAT+ B cells and a7 nAChR+ Kupffer cells interact to drive IL-6 production by Kupffer cells, and another where ChAT+ B cells and a7 nAChR+ hepatic CD8+ T cells interact to reduce IFN? production by CD8+ T cells. Our work offers novel insights into liver regeneration mechanisms that may point to new therapies for liver damage. Overall design: RNA-seq profiling of sorted GFP positive and GFP negative B cells isolated from the liver 4 hours after sham or PHX treated Chat-GFP reporter mice (B6.Cg-Tg(RP23-268L19-EGFP)2Mik/J).