The receptor for urokinase regulates TLR2 mediated inflammatory responses in neutrophils.
The receptor for urokinase regulates TLR2 mediated inflammatory responses in neutrophils.
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尿激酶的受体调节TLR2介导的中性粒细胞中的炎症反应。
DOI：
10.1371/journal.pone.0025843
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Abraham E
中科院分区：
文献类型：
--
作者：
Liu G;Yang Y;Yang S;Banerjee S;De Freitas A;Friggeri A;Davis KI;Abraham E
尿激酶型纤溶酶原激活物受体（uPAR）是一种糖基磷脂酰肌醇（GPI）锚定的膜蛋白，调节尿激酶（uPA）蛋白酶活性、趋化性、细胞-细胞相互作用和凋亡细胞的吞噬作用。uPAR表达在细胞因子或细菌活化的细胞群中增加，包括巨噬细胞和单核细胞。然而，目前还不清楚uPAR是否直接参与炎症细胞如中性粒细胞和巨噬细胞对Toll样受体（TLR）刺激的反应。在这项研究中，我们发现uPAR是TLR 2刺激后最佳中性粒细胞活化所需的，但不是TLR 4刺激。我们发现TLR 2参与uPAR-/-中性粒细胞诱导的TNF-α和IL-6的表达低于uPAR+/+（WT）中性粒细胞。用PI-PLC（其切割GPI部分）预处理中性粒细胞显著降低WT中性粒细胞中TLR 2诱导的TNF-α表达，但在PAM处理的uPAR-/-中性粒细胞中仅显示对TNF-α表达的轻微影响。TLR 2刺激后uPAR-/-或WT中性粒细胞IκB-α降解和NF-κB活化无差异。然而，在TLR 2接合后，uPAR是最佳p38 MAPK激活所必需的。与uPAR调节TLR 2接合诱导的中性粒细胞活化的体外发现一致，我们发现与WT对应物相比，uPAR-/-小鼠中由TLR 2而不是TLR 4刺激诱导的肺部和全身炎症减少。因此，我们的数据表明，中性粒细胞相关的uPAR可能是治疗与严重细菌和其他微生物感染相关的急性炎症、脓毒症和器官损伤的潜在靶点，其中TLR 2参与起主要作用。
The urokinase-type plasminogen activator receptor (uPAR), a glycosylphosphatidylinositol (GPI) anchored membrane protein, regulates urokinase (uPA) protease activity, chemotaxis, cell-cell interactions, and phagocytosis of apoptotic cells. uPAR expression is increased in cytokine or bacteria activated cell populations, including macrophages and monocytes. However, it is unclear if uPAR has direct involvement in the response of inflammatory cells, such as neutrophils and macrophages, to Toll like receptor (TLR) stimulation. In this study, we found that uPAR is required for optimal neutrophil activation after TLR2, but not TLR4 stimulation. We found that the expression of TNF-α and IL-6 induced by TLR2 engagement in uPAR-/- neutrophils was less than that in uPAR+/+ (WT) neutrophils. Pretreatment of neutrophils with PI-PLC, which cleaves GPI moieties, significantly decreased TLR2 induced expression of TNF-α in WT neutrophils, but demonstrated only marginal effects on TNF-α expression in PAM treated uPAR-/- neutrophils. IκB-α degradation and NF-κB activation were not different in uPAR-/- or WT neutrophils after TLR2 stimulation. However, uPAR is required for optimal p38 MAPK activation after TLR2 engagement. Consistent with the in vitro findings that uPAR modulates TLR2 engagement induced neutrophil activation, we found that pulmonary and systemic inflammation induced by TLR2, but not TLR4 stimulation is reduced in uPAR-/- mice compared to WT counterparts. Therefore, our data suggest that neutrophil associated uPAR could be a potential target for treating acute inflammation, sepsis, and organ injury related to severe bacterial and other microbial infections in which TLR2 engagement plays a major role.
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影响因子：
4.4
作者：
Abraham, Edward;Nick, Jerry A.;Dinarello, Charles A.
通讯作者：
Dinarello, Charles A.
影响因子：
64.8
作者：
Foster, Simmie L.;Hargreaves, Diana C.;Medzhitov, Ruslan
通讯作者：
Medzhitov, Ruslan
影响因子：
4.8
作者：
Liu, Gang;Park, Young-Jun;Abraham, Edward
通讯作者：
Abraham, Edward
影响因子：
3.1
作者：
Coleman, JL;Benach, JL
通讯作者：
Benach, JL
DOI：
10.1165/ajrcmb.26.5.4748
发表时间：
2002-05-01
影响因子：
6.4
作者：
Koay, MA;Gao, X;Christman, JW
通讯作者：
Christman, JW