CRTH2 is a critical regulator of neutrophil migration and resistance to polymicrobial sepsis.
CRTH2 is a critical regulator of neutrophil migration and resistance to polymicrobial sepsis.
复制标题
CRTH2是中性粒细胞迁移和对多因素败血症的抗性的关键调节剂。
DOI：
10.4049/jimmunol.1102330
复制
发表时间：
2012-06-01
期刊：
影响因子：
--
通讯作者：
Betsuyaku T
中科院分区：
文献类型：
--
作者：
Ishii M;Asano K;Namkoong H;Tasaka S;Mizoguchi K;Asami T;Kamata H;Kimizuka Y;Fujiwara H;Funatsu Y;Kagawa S;Miyata J;Ishii K;Nakamura M;Hirai H;Nagata K;Kunkel SL;Hasegawa N;Betsuyaku T
虽然花生四烯酸级联反应已被证明与脓毒症有关，但对于前列腺素D2及其新发现的受体——Th2细胞上表达的趋化受体同源分子（CRTH2）在脓毒症反应中的作用知之甚少。严重的脓毒症与中性粒细胞迁移失败有关。为了研究CRTH2是否影响脓毒症时中性粒细胞募集和致死性，我们采用盲肠结扎穿刺（CLP）手术诱导小鼠脓毒症。CRTH2敲除（−/−）小鼠对clp诱导的脓毒症具有高度抗性，这与较低的细菌负荷和较低的TNF-α、IL-6和CCL3的产生有关。抗炎细胞因子IL-10在CRTH2−/−小鼠中升高，减弱了clp诱导的CRTH2−/−小鼠的致死率。CRTH2−/−小鼠CLP后腹膜中性粒细胞积聚更为明显，这与循环中性粒细胞中CXCR2水平升高有关。此外，脓毒症导致WT中性粒细胞中CXCR2启动子处的激活标记组蛋白H3乙酰化水平降低，表明CXCR2的表达水平受到表观遗传调控。最后，中性粒细胞的药理学耗竭和CXCR2的抑制都取消了CRTH2−/−小鼠的生存益处。这些结果表明，基因消融CRTH2可改善严重脓毒症期间受损的中性粒细胞迁移和存活，这与表观遗传介导的CXCR2表达有机制关联。因此，CRTH2是多微生物脓毒症的潜在治疗靶点。
Although arachidonic acid cascade has been shown to be involved in sepsis, little is known about the role of prostaglandin D2 and its newly found receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), on the septic response. Severe sepsis is associated with the failure of neutrophil migration. To investigate whether CRTH2 influences neutrophil recruitment and the lethality during sepsis, sepsis was induced by cecal ligation and puncture (CLP) surgery in mice. CRTH2 knockout (−/−) mice were highly resistant to CLP-induced sepsis, which was associated with lower bacterial load and lower production of TNF-α, IL-6, and CCL3. IL-10, an anti-inflammatory cytokine, was higher in CRTH2−/− mice, blunting CLP-induced lethality in CRTH2−/− mice. Neutrophil accumulation in the peritoneum was more pronounced after CLP in CRTH2−/− mice, which was associated with higher CXCR2 level in circulating neutrophils. Furthermore, sepsis caused a decrease in the level of acetylation of histone H3, an activation mark, at the CXCR2 promoter in WT neutrophils, suggesting that CXCR2 expression levels are epigenetically regulated. Finally, both pharmacological depletion of neutrophils and inhibition of CXCR2 abrogated the survival benefit in CRTH2−/− mice. These results demonstrate that genetic ablation of CRTH2 improved impaired neutrophil migration and survival during severe sepsis, which was mechanistically associated with epigenetic mediated CXCR2 expression. Thus, CRTH2 is a potential therapeutic target for polymicrobial sepsis.
登录
查看更多内容
影响因子：
--
作者：
Kim N;Luster AD
通讯作者：
Luster AD
影响因子：
2.2
作者：
ANDERSON, BO;MOORE, EE;BANERJEE, A
通讯作者：
BANERJEE, A
影响因子：
4.4
作者：
Monneret, G;Li, HP;Powell, WS
通讯作者：
Powell, WS
影响因子：
6
作者：
Cotter, MJ;Norman, KE;Ridger, VC
通讯作者：
Ridger, VC
DOI：
10.1084/jem.193.2.255
发表时间：
2001-01-15
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hirai H;Tanaka K;Yoshie O;Ogawa K;Kenmotsu K;Takamori Y;Ichimasa M;Sugamura K;Nakamura M;Takano S;Nagata K
通讯作者：
Nagata K