LAUSR

BACKGROUND AND AIMS Liver regeneration is vital for the recovery of liver function after hepatectomy. Limited regeneration capacity together with insufficient remnant liver volume is a risk factor for post-hepatectomy liver failure resulting from small-for-size syndrome. Although inflammation plays an important role in controlling liver regeneration, the underlying mechanisms still remain obscure. APPROACH AND RESULTS We identified C-C motif chemokine ligand (CCL) 5 as an important negative regulator for liver regeneration. CCL5 levels were elevated after partial hepatectomy (PHx) both in healthy donors of living donor liver transplantation and PHx mouse models. Ccl5 knockout mice displayed improved survival after 90% PHx and enhanced liver regeneration 36 h after 70% PHx. However, primary hepatocytes from Ccl5-/- mice exposed to growth factors in vitro showed no proliferation advantage compared to those from wild-type mice. Flow cytometry analysis showed the proportions of Ly6Clo macrophages were significantly increased in Ccl5-/- mice after 70% PHx. RNA sequencing analysis revealed that sorted macrophages (CD11b+ Ly6Clo&hi ) manifested enhanced expression of reparative genes in Ccl5-/- mice compared to WT mice. Mechanistically, CCL5 induced macrophages towards pro-inflammatory Ly6Chi phenotype, thereby inhibiting the production of hepatocyte growth factor (HGF) through C-C motif chemokine receptor (CCR) 1- and CCR5-mediated forkhead box O (FoxO) 3a pathway. Finally, blockade of CCL5 greatly optimized survival and boosted liver regeneration in the mouse PHx model. CONCLUSIONS Our findings suggest that inhibition of CCL5 is a promising strategy to improve regeneration restoration by enhancing HGF secretion from reparative macrophages via FoxO3a pathway, which may potentially reduce the mortality of post-hepatectomy liver failure.