Myeloid-Cell Protein Tyrosine Phosphatase-1B Deficiency in Mice Protects Against High-Fat Diet and Lipopolysaccharide-Induced Inflammation, Hyperinsulinemia, and Endotoxemia Through an IL-10 STAT3-Dependent Mechanism
Myeloid-Cell Protein Tyrosine Phosphatase-1B Deficiency in Mice Protects Against High-Fat Diet and Lipopolysaccharide-Induced Inflammation, Hyperinsulinemia, and Endotoxemia Through an IL-10 STAT3-Dependent Mechanism
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DOI：
10.2337/db13-0885
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发表时间：
2014-02-01
期刊：
影响因子：
7.7
通讯作者：
Delibegovic, Mirela
中科院分区：
文献类型：
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作者：
Grant, Louise;Shearer, Kirsty D.;Delibegovic, Mirela
蛋白酪氨酸磷酸酶-1B（PTP 1B）负调控胰岛素和瘦素信号传导，使其成为治疗肥胖诱导的胰岛素抵抗的有吸引力的药物靶点。然而，一些研究表明，由于其潜在的抗炎作用，在靶向巨噬细胞PTP 1B时要谨慎。我们使用髓样细胞（LysM）PTP 1B敲除小鼠（LysM PTP 1B）评估了巨噬细胞PTP 1B在炎症和全身代谢中的作用。LysM PTP 1B小鼠在体内可免受脂多糖（LPS）诱导的内毒素血症和与促炎细胞因子分泌减少相关的肝损伤。在体外，LPS处理的LysM PTP 1B骨髓源性巨噬细胞（BMDM）显示白细胞介素（IL）-10 mRNA表达增加，同时TNF- mRNA水平降低。这些抗炎作用与LysM PTP 1B BMDM中LPS和IL-10诱导的STAT 3磷酸化增加有关。高脂（HF）喂养诱导的慢性炎症导致巨噬细胞PTP 1B缺陷的同样有益的效果; LysM PTP 1B小鼠表现出改善的葡萄糖和胰岛素耐受性，防止LPS诱导的高胰岛素血症，减少巨噬细胞浸润到脂肪组织，并减少肝损伤。HF喂养的LysM PTP 1B小鼠的基础和LPS诱导的IL-10水平升高，与脾细胞中STAT 3磷酸化升高、IL-10 mRNA表达和表达髓系标志物的细胞扩增相关。这些增加的IL-10水平与循环胰岛素和丙氨酸转移酶水平呈负相关。我们的研究表明髓系PTP 1B参与STAT 3/IL-10介导的信号传导的负调节，突出了其作为肥胖症中潜在的抗炎和抗糖尿病靶点的抑制作用。
Protein tyrosine phosphatase-1B (PTP1B) negatively regulates insulin and leptin signaling, rendering it an attractive drug target for treatment of obesity-induced insulin resistance. However, some studies suggest caution when targeting macrophage PTP1B, due to its potential anti-inflammatory role. We assessed the role of macrophage PTP1B in inflammation and whole-body metabolism using myeloid-cell (LysM) PTP1B knockout mice (LysM PTP1B). LysM PTP1B mice were protected against lipopolysaccharide (LPS)-induced endotoxemia and hepatic damage associated with decreased proinflammatory cytokine secretion in vivo. In vitro, LPS-treated LysM PTP1B bone marrow-derived macrophages (BMDMs) displayed increased interleukin (IL)-10 mRNA expression, with a concomitant decrease in TNF- mRNA levels. These anti-inflammatory effects were associated with increased LPS- and IL-10-induced STAT3 phosphorylation in LysM PTP1B BMDMs. Chronic inflammation induced by high-fat (HF) feeding led to equally beneficial effects of macrophage PTP1B deficiency; LysM PTP1B mice exhibited improved glucose and insulin tolerance, protection against LPS-induced hyperinsulinemia, decreased macrophage infiltration into adipose tissue, and decreased liver damage. HF-fed LysM PTP1B mice had increased basal and LPS-induced IL-10 levels, associated with elevated STAT3 phosphorylation in splenic cells, IL-10 mRNA expression, and expansion of cells expressing myeloid markers. These increased IL-10 levels negatively correlated with circulating insulin and alanine transferase levels. Our studies implicate myeloid PTP1B in negative regulation of STAT3/IL-10-mediated signaling, highlighting its inhibition as a potential anti-inflammatory and antidiabetic target in obesity.