NK cell checkpoints and immune therapy in fatty liver disease

摘要

Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis(NAFLD and NASH,respectively)are becoming a global epidemic manifested by metabolic syndrome,hepatic fibrosis,and cirrhosis,as well as hepatocellular carcinoma(HCC).Natural killer(NK)cells play an important role in the natural history of the disease as anti-fibrotic and anti-tumor protection.NK cells directly kill activated myofibroblasts to prevent fibrosis progression.However,NK cell functional impairment develops along with insulin resistance and deterioration to cirrhosis and HCC.Metabolic checkpoints have been identified that affect NK cell function and killing.Insulin resistance has been directly identified within NK cells,as they decrease expression of insulin receptors.The normal NK cell activation by insulin is therefore effected.Furthermore,Nerologin-4(NLG4)is overexpressed in impaired NK cells from NAFLD donors with advanced fibrosis.NLG4 overexpression impairs NK cell function and contributes to fibrosis progression.Intracellular NK cell depletion of mT OR,NMDAR activation by liver environmental enrich agonists up-regulates NLG4 expression.NLG4 causes a downstream cascade of intracellular scaffolding proteins to depress the killing function via f-actin remodeling.Berra neuroxin is a defined ligand for NLG4 and is found in target cells including activated fibrotic myofibroblasts and HCC cells.This overexpression further enhanced the NLG4 effect to impair NK cell killing.Other NK cells immune checkpoints have been identified.Targeting metabolic checkpoints activate NK cells to reconstitute their killing effects as anti-fibrotic or anti-tumor.Moreover,NLG4 NK expression and an occult urea assay with myofibroblasts has been identified as a biomarker tool in fibrogenesis.