Obesity-induced lymphocyte hyperresponsiveness to chemokines: A new mechanism of fatty liver inflammation in obese mice
Obesity-induced lymphocyte hyperresponsiveness to chemokines: A new mechanism of fatty liver inflammation in obese mice
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DOI：
10.1053/j.gastro.2008.02.055
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发表时间：
2008-05-01
期刊：
影响因子：
29.4
通讯作者：
Perlemuter, Gabriel
中科院分区：
文献类型：
--
作者：
Bigorgne, Amelie E.;Bouchet-Delbos, Laurence;Perlemuter, Gabriel
背景与目的：肝脏脂质潴留（脂肪变性）易患肝炎。我们研究了淋巴细胞归巢到脂肪肝的机制和脂多糖（LPS）在ob/ob小鼠炎症发作中的作用。方法：我们通过口服抗生素治疗来减少肠道细菌化合物，以测试内源性LPS在肝脏炎症中的作用。采用淋巴细胞连续转移法研究脂肪变性和淋巴细胞对肝脏炎症的各自贡献。我们测试了淋巴细胞对趋化因子的反应，通过体外趋化试验在ob/ob，他们的瘦对照，和“非肥胖ob/ob”小鼠，通过控制热量摄入来区分肥胖和瘦素缺乏的影响。结果：抗生素治疗可减少CD 4（+）T、CD 8（+）T、自然杀伤（NK）T、B和NK细胞的肝浸润。从ob/ob小鼠或对照小鼠的淋巴细胞连续转移表明：（1）脂肪变性增加了淋巴细胞向肝脏的募集;（2）ob/ob小鼠的CD 4（+）T、CD 8（+）T和B细胞具有更大的特异性迁移至肝脏的倾向。LPS增强了这种迁移。在高脂饮食诱导的肥胖模型中也观察到了这些结果。CD 4 + T和B细胞分别对CXCL 12和CXCL 13有高反应性。体重正常化的“非肥胖ob/ob”小鼠减少了肝脏炎症，淋巴细胞对趋化因子的反应，并归巢到肝脏。结论：我们的研究提供了第一个证据，即遗传性或饮食诱导的肥胖小鼠的肝脏炎症是由脂肪变性和淋巴细胞对肝脏中表达的趋化因子的高反应性引起的。这些异常是可逆的体重正常化。
Background & Aims: Hepatic lipid retention (steatosis) predisposes hepatitis. We investigated the mechanisms of lymphocyte homing to fatty liver and the role of lipopolysaccharide (LPS) in the onset of inflammation in ob/ob mice. Methods: We decreased intestinal bacterial compounds by oral antibiotic treatment to test the role of endogenous LPS in liver inflammation. Adoptive transfer of lymphocytes was used to study the respective contributions of steatosis and lymphocytes to liver inflammation. We tested lymphocyte response to chemokines by in vitro chemotaxis assays in ob/ob, their lean controls, and "non-obese ob/ob" mice, generated by controlling caloric intake to distinguish between the effects of obesity and leptin deficiency. Results: Antibiotic treatment decreased liver infiltration with CD4(+) T, CD8(+) T, natural killer (NK)T, B, and NK cells. Adoptive transfer of lymphocytes from ob/ob or control mice showed that (1) steatosis increased lymphocyte recruitment to the liver; (2) CD4(+) T, CD8(+) T, and B cells from ob/ob mice had a greater propensity to migrate specifically to the liver. This migration was enhanced by LPS. These results were also observed in a model of high-fat diet-induced obesity. CD4+ T and B cells were hyperresponsive to CXCL12 and CXCL13, respectively. Weight normalization in "non-obese ob/ob" mice decreased liver inflammation, lymphocyte response to chemokines, and homing to the liver. Conclusions: Our study provides the first evidence that liver inflammation in mice with genetic or diet-induced obesity results from both steatosis and lymphocyte hyperresponsiveness to chemokines expressed in the liver. These abnormalities are reversible with weight normalization.