IRAK1-dependent signaling mediates mortality in polymicrobial sepsis.
IRAK1-dependent signaling mediates mortality in polymicrobial sepsis.
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DOI：
10.1007/s10753-013-9692-1
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发表时间：
2013-12
期刊：
影响因子：
5.1
通讯作者：
Spolarics, Zoltan
中科院分区：
文献类型：
--
作者：
Chandra, Rachna;Federici, Stephanie;Bishwas, Tripti;Nemeth, Zoltan H.;Deitch, Edwin A.;Thomas, James A.;Spolarics, Zoltan
IRAK1 是炎症反应过程中 TLR/IL1R 介导的细胞激活的关键调节蛋白。研究表明，根据所用炎症模型的性质，IRAK1 的下调可能是有益的，也可能是有害的。然而，IRAK1 在影响多种微生物脓毒症结局中的作用尚不清楚。我们使用 IRAK1 缺陷小鼠品系和盲肠结扎穿刺 (CLP) 程序测试了这个问题，这是一种临床相关的啮齿动物败血症模型。与 WT (85%) 相比，IRAK1 缺陷小鼠 (35%) 脓毒症引起的死亡率明显较低。与 WT 相比，IRAK1 缺乏症患者 CLP 后 6 小时脓毒症引起的血液 IL-6 和 IL-10 水平升高减弱，但细胞因子水平在 CLP 后 20 小时相似。与 WT 相比，IRAK1 缺陷小鼠中脓毒症诱导的血液粒细胞增多和脾 B 细胞消耗也减弱。对IRAK1缺陷型和WT巨噬细胞的TLR介导的细胞因子反应的离体分析表明，IRAK1缺陷型中IL-6和IL1β的TLR4依赖性下调，而TLR2依赖性反应不受影响。与 WT 相比，IRAK1 巨噬细胞中 TLR7/8 介导的 IL-6、IL1β 和 IL-10 产生也减弱。研究表明，IRAK1 缺陷会影响多种 TLR 依赖性途径，并降低多种微生物败血症后的早期细胞因子反应。 IRAK1 表达缺失引起的炎症反应延迟是有益的，因为它表明多种微生物败血症后的生存机会显着增加。
IRAK1 is a key regulatory protein in TLR/IL1R-mediated cell activation during the inflammatory response. Studies indicated that pending on the nature of the used inflammatory model, down-regulation of IRAK1 may be beneficial or detrimental. However the role of IRAK1 in affecting outcome in polymicrobial sepsis is unknown. We tested this question using an IRAK1 deficient mouse strain and the cecal ligation and puncture (CLP) procedure, which is a clinically relevant rodent septic model. Sepsis-induced mortality was markedly lower in IRAK1-deficient mice (35%) compared to WT (85%). Sepsis-induced increases in blood IL-6 and IL-10 levels were blunted at 6h post-CLP in IRAK1 deficiency compared to WT but cytokine levels were similar at 20h post-CLP. Sepsis induced blood granulocytosis and depletion of splenic B cells were also blunted in IRAK1 deficient mice as compared to WT. Analysis of TLR-mediated cytokine responses by IRAK1 deficient and WT macrophages ex vivo indicated a TLR4-dependent down-regulation of IL-6 and IL1β in IRAK1 deficiency, whereas TLR2 dependent responses were unaffected. TLR7/8-mediated IL-6, IL1β and IL-10 production was also blunted in IRAK1 macrophages as compared to WT. The study shows that IRAK1 deficiency impacts multiple TLR-dependent pathways and decreases early cytokine responses following polymicrobial sepsis. The delayed inflammatory response caused by the lack of IRAK1 expression is beneficial, as it manifests a markedly increased chance of survival after polymicrobial sepsis.
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影响因子：
3.1
作者：
Remick, DG;Bolgos, G;Siddiqui, J
通讯作者：
Siddiqui, J
DOI：
10.4049/jimmunol.1102181
发表时间：
2012-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Liu YC;Simmons DP;Li X;Abbott DW;Boom WH;Harding CV
通讯作者：
Harding CV
DOI：
10.1164/rccm.200603-341oc
发表时间：
2006-06-15
影响因子：
24.7
作者：
Arcaroli, John;Silva, Eliezer;Abraham, Edward
通讯作者：
Abraham, Edward
影响因子：
5.5
作者：
Chandra, Rachna;Villanueva, Erika;Spolarics, Zoltan
通讯作者：
Spolarics, Zoltan
影响因子：
4.4
作者：
Chandra, Rachna;Federici, Stephanie;Spolarics, Zoltan
通讯作者：
Spolarics, Zoltan