Calcium/Calmodulin-dependent Protein Kinase Kinase 2 Regulates Macrophage-mediated Inflammatory Responses
Calcium/Calmodulin-dependent Protein Kinase Kinase 2 Regulates Macrophage-mediated Inflammatory Responses
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DOI：
10.1074/jbc.m111.336032
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发表时间：
2012-03-30
影响因子：
4.8
通讯作者：
Means, Anthony R.
中科院分区：
文献类型：
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作者：
Racioppi, Luigi;Noeldner, Pamela K.;Means, Anthony R.
钙/钙调蛋白依赖的激酶2(CAMKK2)在调节食物摄入和能量消耗方面起着关键作用，至少部分是通过对下丘脑神经元的作用来实现的。此前，我们发现丢失CAMKK2可以保护小鼠免受高脂饮食(HFD)诱导的肥胖和糖耐量异常的影响。然而，尽管给WT小鼠配对喂食HFD来匹配CAMKK2基因缺失小鼠的食物摄入量可以减缓体重增加，但它无法防止葡萄糖耐量不足。在这里，我们表明，相对于WT小鼠，高脂饲料喂养的CAMKK2缺失小鼠免受脂肪炎症的保护，并保持葡萄糖耐量。此外，CAMKK2的缺失还可以保护小鼠免受内毒素休克和暴发性肝炎的影响。我们研究了CAMKK2在免疫细胞中的表达，发现它仅限于单核/巨噬细胞系的表达。CAMKK2缺失的巨噬细胞在Toll样受体4(TLR4)激动剂脂多糖(LPS)刺激下，对细菌的扩散、吞噬和细胞因子的合成表现出明显的缺陷。从机制上讲，CAMKK2的丢失使TLR4从蛋白酪氨酸激酶2(PYK2；也称为PTK2B)的激活中解偶联。我们的发现揭示了CAMKK2在控制巨噬细胞对过量营养或病原体衍生物的炎症反应幅度的中介机制中的一个重要功能。
Calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) plays a key role in regulating food intake and energy expenditure at least in part by its actions in hypothalamic neurons. Previously, we showed that loss of CaMKK2 protected mice from high-fat diet (HFD)-induced obesity and glucose intolerance. However, although pair feeding HFD to WT mice to match food consumption of CAMKK2-null mice slowed weight gain, it failed to protect from glucose intolerance. Here we show that relative to WT mice, HFD-fed CaMKK2-null mice are protected from inflammation in adipose and remain glucose-tolerant. Moreover, loss of CaMKK2 also protected mice from endotoxin shock and fulminant hepatitis. We explored the expression of CaMKK2 in immune cells and found it to be restricted to those of the monocyte/macrophage lineage. CaMKK2-null macrophages exhibited a remarkable deficiency to spread, phagocytose bacteria, and synthesize cytokines in response to the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS). Mechanistically, loss of CaMKK2 uncoupled the TLR4 cascade from activation of protein tyrosine kinase 2 (PYK2; also known as PTK2B). Our findings uncover an important function for CaMKK2 in mediating mechanisms that control the amplitude of macrophage inflammatory responses to excess nutrients or pathogen derivatives.