Dysregulated TLR3-dependent signaling and innate immune activation in superoxide-deficient macrophages from nonobese diabetic mice.
Dysregulated TLR3-dependent signaling and innate immune activation in superoxide-deficient macrophages from nonobese diabetic mice.
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DOI：
10.1016/j.freeradbiomed.2012.01.027
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发表时间：
2012-05-01
影响因子：
7.4
通讯作者：
Tse, Hubert M.
中科院分区：
文献类型：
--
作者：
Seleme, Maria C.;Lei, Weiqi;Burg, Ashley R.;Goh, Kah Yong;Metz, Allison;Steele, Chad;Tse, Hubert M.
关键词：
在1型糖尿病（T1D）中，巨噬细胞和其他先天免疫细胞产生的活性氧（ROS）和促炎细胞因子破坏胰腺β细胞，同时促进自身反应性T细胞成熟。超氧缺陷非肥胖糖尿病小鼠（NOD.Ncf1m1J）对自发性糖尿病具有抵抗性，揭示了ros信号在T1D中的整体作用。在这里，我们评估了NOD和NOD的骨髓源性巨噬细胞（bm - m φ）的先天免疫激活状态。Ncf1m1J小鼠在poly（I:C）诱导的toll样受体3 （TLR3）信号传导后。我们发现，ROS的合成是NF-κB信号通路的有效激活以及TLR3和同源接头分子TRIF的伴随表达所必需的。保利(我:C)刺激点头。与NOD bm - m - φ相比，Ncf1m1J bm - m - φ分别表现出TNF-α和IFN-β促炎细胞因子合成减少2倍和10倍。IFN-α/β的最佳表达并不仅仅依赖于超氧化物合成，而是需要p47phox以不依赖nox的方式发挥作用来介导I型干扰素合成。有趣的是，CD4 T细胞活化所需的MHC-II I-Ag7表达相对NOD增加了2倍，暗示超氧化物在I-Ag7下调中的作用。这些发现表明先天免疫模式识别受体激活缺陷和随后自身反应性T细胞成熟所需的TNF-α和IFN-β促炎细胞因子合成减少可能有助于NOD中观察到的T1D保护。Ncf1m1J老鼠。
In Type 1 diabetes (T1D), reactive oxygen species (ROS) and pro-inflammatory cytokines produced by macrophages and other innate immune cells destroy pancreatic β-cells while promoting autoreactive T cell maturation. Superoxide-deficient Non-Obese Diabetic mice (NOD.Ncf1m1J) are resistant to spontaneous diabetes, revealing the integral role of ROS-signaling in T1D. Here, we evaluate the innate immune activation state of bone marrow-derived macrophages (BM-Mϕ) from NOD and NOD.Ncf1m1J mice after poly(I:C)-induced Toll-like receptor 3 (TLR3) signaling. We show that ROS synthesis is required for efficient activation of the NF-κB signaling pathway and concomitant expression of TLR3 and the cognate adaptor molecule, TRIF. Poly(I:C)-stimulated NOD.Ncf1m1J BM-Mϕ exhibited a 2- and 10-fold decrease in TNF-α and IFN-β pro-inflammatory cytokine synthesis, respectively, in contrast to NOD BM-Mϕ. Optimal expression of IFN-α/β is not solely dependent on superoxide synthesis, but requires p47phox to function in a NOX-independent manner to mediate Type I interferon synthesis. Interestingly, MHC-II I-Ag7 expression necessary for CD4 T cell activation is increased 2-fold relative to NOD, implicating a role for superoxide in I-Ag7 down-regulation. These findings suggest that defective innate immune pattern-recognition receptor activation and subsequent decrease in TNF-α and IFN-β pro-inflammatory cytokine synthesis necessary for autoreactive T cell maturation, may contribute to the T1D protection observed in NOD.Ncf1m1J mice.
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影响因子：
7
作者：
Choi NM;Majumder P;Boss JM
通讯作者：
Boss JM
影响因子：
4.4
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TAYLOR, KW