B cell-derived acetylcholine promotes liver regeneration by regulating Kupffer cell and hepatic CD8+ T cell function

Abstract

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⁺ B cells subjected to partial hepatectomy (PHX) displayed greater mortality due to failed LR. Kupffer cells and hepatic CD8⁺ 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⁺ T cells to curtail harmful interferon-gamma (IFNγ) production. Our work offers insights into LR mechanisms that may point to therapies for liver damage.

Keywords: B cells; CD8 T cells; ChAT B cells; IL-6; Kupffer cells; acetylcholine; hepatic repair; liver regeneration; partial hepatectomy; α7 nAChR; α7 nicotinic acetylcholine receptor.