Dewei Ye1, Kangmin Yang2, Shufei Zang3, Zhuofeng Lin4, Hau-Tak Chau5, Yudong Wang6, Jialiang Zhang7, Junping Shi3, Aimin Xu8, Shaoqiang Lin9, Yu Wang10. 1. Joint Institute of Metabolic Medicine between State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong and Jinan University, Guangzhou, China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China. 2. Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China. 3. Department of Liver Diseases, Hangzhou Normal University Affiliated Hospital, Hangzhou, China. 4. Joint Institute of Metabolic Medicine between State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong and Jinan University, Guangzhou, China. 5. Department of Medicine, The University of Hong Kong, Hong Kong, China. 6. State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China. 7. State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China. 8. Joint Institute of Metabolic Medicine between State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong and Jinan University, Guangzhou, China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China. Electronic address: amxu@hku.hk. 9. Joint Institute of Metabolic Medicine between State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong and Jinan University, Guangzhou, China; Central Laboratory of the First Affiliated Hospital of Jinan University, Guangzhou, China. Electronic address: shaotsiang@163.com. 10. Joint Institute of Metabolic Medicine between State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong and Jinan University, Guangzhou, China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China. Electronic address: yuwanghk@hku.hk.
Abstract
BACKGROUND & AIMS: Inflammatory cell infiltration in the liver is a hallmark of non-alcoholic steatohepatitis (NASH). However, the pathological events which trigger the infiltration of inflammatory cells to mediate NASH pathogenesis remains poorly understood. This study aims to investigate the role of neutrophil-derived lipocalin 2 (LCN2) in mediating the transition from simple steatosis to NASH. METHODS: Animal models of NASH were induced by high fat high cholesterol (HFHC) diet and methionine- and choline-deficient (MCD) diet in LCN2 knockout mice and wild-type controls. RESULTS: Circulating levels of LCN2 and its hepatic expression were markedly increased in both murine models and human subjects with NASH, and these changes were associated with increased infiltration of neutrophils. In diet-induced NASH models, hepatic injury, necroinflammation and infiltration of neutrophils and macrophages were substantially attenuated by genetic depletion of LCN2. In contrast, chronic infusion of recombinant LCN2 exacerbated diet-induced liver injury, inflammation and macrophage accumulation in a neutrophil-dependent manner. Primary mouse neutrophils lacking LCN2 exhibited a defective migration capacity, which can be reversed by replenishment with recombinant LCN2. Mechanistically, LCN2 induced the expression of the chemokine (C-X-C motif) receptor 2 (CXCR2), thereby leading to activation of ERK1/2 and production of proinflammatory chemokines. LCN2-induced inflammation, infiltration of macrophages and liver injury was abrogated in CXCR2-deficient mice. CONCLUSIONS: These findings demonstrated that LCN2 acts as a central mediator to facilitate the crosstalk between neutrophils and hepatic macrophages via induction of the chemokine receptor CXCR2, thereby exacerbating steatohepatitis. LAY SUMMARY: Lipocalin-2 levels in blood and the liver were markedly increased in both mouse models and human subjects with NASH, and these changes were associated with increased infiltration of neutrophils in the liver. In diet-induced NASH models, hepatic injury, necroinflammation and infiltration of neutrophils and macrophages were substantially attenuated by genetic depletion of lipocalin-2, but was augmented by chronic infusion of recombinant lipocalin-2. Lipocalin-2 induced the expression of the chemokine receptor CXCR2, thereby leading to activation of the mitogen-activated protein (MAP) kinase ERK1/2 and production of proinflammatory chemokines. Lipocalin-2-induced inflammation, infiltration of macrophages and liver injury was abrogated in CXCR2-deficient mice.
BACKGROUND & AIMS: Inflammatory cell infiltration in the liver is a hallmark of non-alcoholic steatohepatitis (NASH). However, the pathological events which trigger the infiltration of inflammatory cells to mediate NASH pathogenesis remains poorly understood. This study aims to investigate the role of neutrophil-derived lipocalin 2 (LCN2) in mediating the transition from simple steatosis to NASH. METHODS: Animal models of NASH were induced by high fat high cholesterol (HFHC) diet and methionine- and choline-deficient (MCD) diet in LCN2 knockout mice and wild-type controls. RESULTS: Circulating levels of LCN2 and its hepatic expression were markedly increased in both murine models and human subjects with NASH, and these changes were associated with increased infiltration of neutrophils. In diet-induced NASH models, hepatic injury, necroinflammation and infiltration of neutrophils and macrophages were substantially attenuated by genetic depletion of LCN2. In contrast, chronic infusion of recombinant LCN2 exacerbated diet-induced liver injury, inflammation and macrophage accumulation in a neutrophil-dependent manner. Primary mouse neutrophils lacking LCN2 exhibited a defective migration capacity, which can be reversed by replenishment with recombinant LCN2. Mechanistically, LCN2 induced the expression of the chemokine (C-X-C motif) receptor 2 (CXCR2), thereby leading to activation of ERK1/2 and production of proinflammatory chemokines. LCN2-induced inflammation, infiltration of macrophages and liver injury was abrogated in CXCR2-deficientmice. CONCLUSIONS: These findings demonstrated that LCN2 acts as a central mediator to facilitate the crosstalk between neutrophils and hepatic macrophages via induction of the chemokine receptor CXCR2, thereby exacerbating steatohepatitis. LAY SUMMARY:Lipocalin-2 levels in blood and the liver were markedly increased in both mouse models and human subjects with NASH, and these changes were associated with increased infiltration of neutrophils in the liver. In diet-induced NASH models, hepatic injury, necroinflammation and infiltration of neutrophils and macrophages were substantially attenuated by genetic depletion of lipocalin-2, but was augmented by chronic infusion of recombinant lipocalin-2. Lipocalin-2 induced the expression of the chemokine receptor CXCR2, thereby leading to activation of the mitogen-activated protein (MAP) kinase ERK1/2 and production of proinflammatory chemokines. Lipocalin-2-induced inflammation, infiltration of macrophages and liver injury was abrogated in CXCR2-deficientmice.
Authors: Dirk J van der Windt; Vikas Sud; Hongji Zhang; Patrick R Varley; Julie Goswami; Hamza O Yazdani; Samer Tohme; Patricia Loughran; Robert M O'Doherty; Marta I Minervini; Hai Huang; Richard L Simmons; Allan Tsung Journal: Hepatology Date: 2018-07-16 Impact factor: 17.425