Lipocalin-2 mediates non-alcoholic steatohepatitis by promoting neutrophil-macrophage crosstalk via the induction of CXCR2

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• 作者：Dewei Ye¹ ; ² ; ³ ; Kangmin Yang⁴ ; Shufei Zang⁵ ; Zhuofeng Lin¹ ; Hau-Tak Chau³ ; Yudong Wang² ; Jialiang Zhang² ; ³ ; Junping Shi⁵ ; Aimin Xu¹ ; ² ; ³ ; ^{amxu@hku.hk" class="auth_mail" title="E-mail the corresponding author} ; Shaoqiang Lin¹ ; ⁶ ; ^{shaotsiang@163.com" class="auth_mail" title="E-mail the corresponding author} ; Yu Wang¹ ; ² ; ⁴ ; ^{yuwanghk@hku.hk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ALT ; alanine aminotransferase ; ASH ; alcoholic steatohepatitis ; AST ; aspartate transaminase ; AKO ; ApoE knockout ; BMT ; bone marrow transplantation ; CXCL2 ; CXC chemokine ligand-2 ; CXCR2 ; (C-X-C motif) receptor 2 ; DKO ; ApoE-LCN2 double knockout ; ERK ; extracellular signal-regulated kinase ; HFHC ; high fat high cholesterol ; IL-1β ; interleukin 1β ; LCN2 ; lipocalin 2 ; MCD ; methionine- and choline-deficient diet ; NASH ; non-alcoholic steatohepatitis ; NPC ; non-parenchymal cell ; MCP-1 ; monocyte chemoattractan
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：65
• 期：5
• 页码：988-997
• 全文大小：2891 K

文摘

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.