Adoptive Transfer of Heme Oxygenase-1 (HO-1)-Modified Macrophages Rescues the Nuclear Factor Erythroid 2-Related Factor (Nrf2) Antiinflammatory Phenotype in Liver Ischemia/Reperfusion Injury
Adoptive Transfer of Heme Oxygenase-1 (HO-1)-Modified Macrophages Rescues the Nuclear Factor Erythroid 2-Related Factor (Nrf2) Antiinflammatory Phenotype in Liver Ischemia/Reperfusion Injury
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DOI：
10.2119/molmed.2014.00103
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发表时间：
2014-07-01
影响因子：
5.7
通讯作者：
Kupiec-Weglinski, Jerzy W.
中科院分区：
文献类型：
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作者：
Huang, Jing;Shen, Xiu-Da;Kupiec-Weglinski, Jerzy W.
巨噬细胞在肝脏缺血/再灌注损伤（IRI）的病理生理学中起重要作用。虽然Nrf 2调节巨噬细胞特异性血红素加氧酶-1（HO-1）的抗氧化防御，但HO-1诱导是否可以拯救巨噬细胞Nrf 2依赖性的抗氧化功能仍不清楚。本研究探讨了Nrf 2-HO-1轴在过继转移过表达HO-1的骨髓源性巨噬细胞（BTH）后调节无菌肝脏炎症反应的机制。用Ad-HO-1 β-半乳糖苷预处理的Nrf 2缺陷小鼠的肝脏改善了肝脏IRI（90分钟热缺血后再灌注6小时），这一点通过改善肝细胞功能（血清丙氨酸氨基转移酶[sALT]水平）和保留肝脏结构（Suzuki组织学评分）得到证实。用Ad-HO-1 Bp 53治疗可减少缺血性肝脏中的中性粒细胞积聚、促炎介质和肝细胞坏死/凋亡。此外，Ad-HO-1转染Nrf 2-缺陷型Bcl-2抑制M1（Nos 2（+）），同时促进M2（Mrc-1/Arg-1（+））表型。与对照组不同，Ad-HO-1 Bcl 3在IR应激的Nrf 2缺陷的肝脏以及脂多糖（LPS）刺激的Bcl 3中增加Notch 1、Hes 1、Stat 3和Akt的磷酸化的表达。因此，过继转移离体产生的Ad-HO-1 Bp 53通过促进Notch 1/Hes 1/Stat 3信号传导和将巨噬细胞重编程为M2表型来挽救Nrf 2依赖性Bp 53表型。这些发现为一种新的具有临床吸引力的策略提供了理论基础，以管理IR肝脏炎症/损伤。
Macrophages are instrumental in the pathophysiology of liver ischemia/reperfusion injury (IRI). Although Nrf2 regulates macrophage-specific heme oxygenase-1 (HO-1) antioxidant defense, it remains unknown whether HO-1 induction might rescue macrophage Nrf2-dependent antiinflammatory functions. This study explores the mechanisms by which the Nrf2-HO-1 axis regulates sterile hepatic inflammation responses after adoptive transfer of ex vivo modified HO-1 overexpressing bone marrow-derived macrophages (BMMs). Livers in Nrf2-deficient mice preconditioned with Ad-HO-1 BMMs, but not Ad-beta-GalBMMs, ameliorated liver IRI (at 6 h of reperfusion after 90 min of warm ischemia), evidenced by improved hepatocellular function (serum alanine aminotransferase [sALT] levels) and preserved hepatic architecture (Suzuki histological score). Treatment with Ad-HO-1 BMMs decreased neutrophil accumulation, proinflammatory mediators and hepatocellular necrosis/apoptosis in ischemic livers. Moreover, Ad-HO-1 transfection of Nrf2-deficient BMMs suppressed M1 (Nos2(+)) while promoting the M2 (Mrc-1/Arg-1(+)) phenotype. Unlike in controls, Ad-HO-1 BMMs increased the expression of Notch1, Hes1, phosphorylation of Stat3 and Akt in IR-stressed Nrf2-deficient livers as well as in lipopolysaccharide (LPS)-stimulated BMMs. Thus, adoptive transfer of ex vivo generated Ad-HO-1 BMMs rescued Nrf2-dependent antiinflammatory phenotype by promoting Notch1/Hes1/Stat3 signaling and reprogramming macrophages toward the M2 phenotype. These findings provide the rationale for a novel clinically attractive strategy to manage IR liver inflammation/damage.