Semaphorin 7a is protective through immune modulation during acetaminophen-induced liver injury: Semaphorin 7a is protective in acute liver injury

BACKGROUND AND AIM: Acetaminophen (APAP) induced acute liver injury (ALI), the leading cause acute liver failure in the western world, has limited treatment options. APAP toxicity results in massive hepatic necrosis and secondary infiltrating monocytes and neutrophils, which contribute to pathogenesis. Semaphorin 7a (Sema7a), a chemoattractant and modulator of monocytes and neutrophils, is a potential therapeutic target in other conditions, but its role in APAP-ALI is unexplored.

METHODS: Wild-type (WT) and Sema7a knockout (KO) mice were examined during APAP-ALI. Serum liver function tests, histological analysis and cellular localisation of Sema7a and its receptors, Plexin C1 and Integrin β1, were examined. Serum cytokines were quantified, tissue macrophages and neutrophils were localised, and in vivo phenotype, including phagocytosis, was assessed by immunohistochemistry and flow cytometry.

RESULTS: Sema7a was expressed by HNF4α + peri-necrotic hepatocytes circumferentially during APAP-ALI injury phases, and serum concentrations were increased, and correlated with hepatic injury. Sema7a KO mice had increased circulating inflammatory cytokines and significantly less hepatic F4/80 + macrophages, a cell type required for hepatic repair. Sema7a KO mice had higher necrotic area neutrophils, and increased neutrophil chemoattractant CXCL1. Without Sema7a expression, mice displayed increased necrosis and liver injury markers compared to Sema7a WT mice. Without peri-necrotic hepatocyte Sema7a expression, we also identified increased cell death and hepatic cellular stress outside of necrosis.

CONCLUSION: We have identified a novel protective role of Sema7a during injury phases of APAP-ALI. Without peri-necrotic hepatocyte Sema7a expression and secretion, there is increased inflammation, time specific worsened hepatic necrosis and increased hepatic cell stress and death outside of the necrotic zone.