Deficiency in Toll-interacting protein (Tollip) skews inflamed yet incompetent innate leukocytes in vivo during DSS-induced septic colitis.
Deficiency in Toll-interacting protein (Tollip) skews inflamed yet incompetent innate leukocytes in vivo during DSS-induced septic colitis.
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DOI：
10.1038/srep34672
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发表时间：
2016-10-05
影响因子：
4.6
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Diao N;Zhang Y;Chen K;Yuan R;Lee C;Geng S;Kowalski E;Guo W;Xiong H;Li M;Li L
功能受损的中性粒细胞有助于严重炎症和损伤（如结肠炎和败血症）患者的不良临床结果。然而，功能失调的中性粒细胞在脓毒性结肠炎中的发生机制仍然知之甚少。我们报道功能失调的中性粒细胞可能是由toll相互作用蛋白（Tollip）的抑制引起的。我们观察到Tollip缺陷的中性粒细胞对细菌产物fMLF的迁移能力受到损害，这是由于AKT活性和FPR2活性的降低，产生杀死细菌的中性粒细胞胞外陷阱（NET）的潜力降低，以及杀死细菌的活性受损。另一方面，Tollip缺陷中性粒细胞的CCR5水平升高，CCR5负责它们归巢到无菌炎症组织。在dss诱导结肠炎的Tollip缺陷小鼠体内也观察到炎症和无能的中性粒细胞表型。我们观察到，TUDCA是一种能够恢复Tollip细胞功能的化合物，可以有效减轻dss诱导的结肠炎的严重程度。在人类中，我们观察到，与健康献血者的血液样本相比，从人类结肠炎患者收集的外周血中Tollip水平显著降低。总的来说，我们的数据揭示了Tollip改变的新机制，该机制是中性粒细胞炎症和无能极化导致结肠炎严重后果的基础。
Functionally compromised neutrophils contribute to adverse clinical outcomes in patients with severe inflammation and injury such as colitis and sepsis. However, the ontogeny of dysfunctional neutrophil during septic colitis remain poorly understood. We report that the dysfunctional neutrophil may be derived by the suppression of Toll-interacting-protein (Tollip). We observed that Tollip deficient neutrophils had compromised migratory capacity toward bacterial product fMLF due to reduced activity of AKT and reduction of FPR2, reduced potential to generate bacterial-killing neutrophil extra-cellular trap (NET), and compromised bacterial killing activity. On the other hand, Tollip deficient neutrophils had elevated levels of CCR5, responsible for their homing to sterile inflamed tissues. The inflamed and incompetent neutrophil phenotype was also observed in vivo in Tollip deficient mice subjected to DSS-induced colitis. We observed that TUDCA, a compound capable of restoring Tollip cellular function, can potently alleviate the severity of DSS-induced colitis. In humans, we observed significantly reduced Tollip levels in peripheral blood collected from human colitis patients as compared to blood samples from healthy donors. Collectively, our data reveal a novel mechanism in Tollip alteration that underlies the inflamed and incompetent polarization of neutrophils leading to severe outcomes of colitis.
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DOI：
10.1146/annurev-pathol-020712-164023
发表时间：
2014
期刊：
Annual review of pathology
影响因子：
--
作者：
Mayadas TN;Cullere X;Lowell CA
通讯作者：
Lowell CA
影响因子：
4.8
作者：
Baker, Bianca;Geng, Shuo;Li, Liwu
通讯作者：
Li, Liwu
影响因子：
4.4
作者：
Maitra, Urmila;Deng, Hui;Li, Liwu
通讯作者：
Li, Liwu
影响因子：
44.1
作者：
Remijsen, Quinten;Vanden Berghe, Tom;Vandenabeele, Peter
通讯作者：
Vandenabeele, Peter
抑制白介素1受体/TOLL样受体信号传导通过剪接的短形式的MyD88抑制是由于其未能募集IRAK-4所致。
影响因子：
15.3
作者：
Burns, K;Janssens, S;Brissoni, B;Olivos, N;Beyaert, R;Tschopp, J
通讯作者：
Tschopp, J