Dysregulated Toll-like receptor expression and signaling in bone marrow-derived macrophages at the onset of diabetes in the non-obese diabetic mouse
Dysregulated Toll-like receptor expression and signaling in bone marrow-derived macrophages at the onset of diabetes in the non-obese diabetic mouse
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DOI：
10.1093/intimm/dxl045
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发表时间：
2006-07-01
影响因子：
4.4
通讯作者：
McInerney, Marcia F.
中科院分区：
文献类型：
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作者：
Mohammad, Mohammad K.;Morran, Michael;McInerney, Marcia F.
研究了小鼠骨髓源性巨噬细胞（BM-0）Toll样受体（TLR）在糖尿病发生前后的表达、反应性和调节。TLR 3和TLR 5的表达在新发糖尿病非肥胖糖尿病（NOD）小鼠中显著高于糖尿病前期和对照小鼠品系。TLR 3配体poly（I）poly（C）在NOR和糖尿病前期NOD中触发其自身受体的上调，但TLR 3在糖尿病NOD小鼠中已经高度表达。TLR 3的表达水平与poly（I）poly（C）触发的IFN活性相关。LPS引发糖尿病前期NOD、NOR和BALB/c小鼠TLR 4下调，而1型糖尿病NOD和2型糖尿病NZL小鼠TLR 4水平持续升高。糖尿病状态下TLR 4表达失调与核因子κ B（NF-κ B B）对TLR 4配体LPS的反应性活化增加以及IL-12 p40、肿瘤坏死因子α（TNF α）、IL-6和诱导型一氧化氮合酶的高表达相关，但IL-10的表达降低。NOD小鼠的骨髓前体细胞在分化为巨噬细胞的过程中暴露于高血糖环境导致TLR 2和TLR 4以及细胞因子TNF α水平升高。结果表明，巨噬细胞前体细胞受到糖尿病全身变化的影响，有利于TLR表达和敏感性的改变，这可能会影响巨噬细胞介导的糖尿病并发症的易感性，并解释糖尿病感染的不适当反应。
The expression, responsiveness and regulation of mouse Toll-like receptors (TLRs) in bone marrow-derived macrophages (BM-O) were investigated prior to and following the development of diabetes. Expression of TLR3 and TLR5 was significantly higher in newly diabetic non-obese diabetic (NOD) mice when compared with pre-diabetic and control strains of mice. The TLR3 ligand poly(I)poly(C) triggered up-regulation of its own receptor in NOR and pre-diabetic NOD, but TLR3 was already highly expressed in diabetic NOD mice. Expression levels of TLR3 correlated with poly(I)poly(C)-triggered IFN activity. LPS triggered down-regulation of TLR4 in pre-diabetic NOD, NOR and BALB/c, while levels of TLR4 remained consistently elevated in type 1 diabetic NOD and type 2 diabetic NZL mice. Dysregulation of TLR4 expression in the diabetic state correlated with increased nuclear factor kappa B (NF-kappa B) activation in response to the TLR4 ligand LPS and higher expression of IL-12p40, tumor necrosis factor alpha (TNF alpha), IL-6 and inducible nitric oxide synthase but lowered expression of IL-10. Exposure of bone marrow precursor cells from NOD mice to a hyperglycemic environment during differentiation into macrophages resulted in elevated levels of TLR2 and TLR4 and the cytokine TNF alpha. The results indicate that macrophage precursors are influenced by systemic changes in diabetes favoring altered TLR expression and sensitivity that may influence susceptibility to macrophage-mediated diabetes complications and explain inappropriate responses to infection in diabetes.