Impaired neutrophil chemotaxis in sepsis associates with GRK expression and inhibition of actin assembly and tyrosine phosphorylation
Impaired neutrophil chemotaxis in sepsis associates with GRK expression and inhibition of actin assembly and tyrosine phosphorylation
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DOI：
10.1182/blood-2006-05-024638
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发表时间：
2006-11-01
期刊：
影响因子：
20.3
通讯作者：
Cunha, Fernando Q.
中科院分区：
文献类型：
--
作者：
Arraes, Sandra Mara A.;Freitas, Marta S.;Cunha, Fernando Q.
脓毒症期间炎症反应的解除似乎反映了抑制白细胞功能的介质的过量产生。我们研究了严重脓毒症患者中性粒细胞无法向趋化剂迁移的细胞内机制。脓毒症患者（52例）和15名志愿者被前瞻性纳入研究。患者表现为肿瘤坏死因子-a、干扰素- γ、白细胞介素-8和白细胞介素-10的循环水平升高。患者对甲氧基-蛋氨酸-亮基-苯丙氨酸（FMLP）、白三烯B-4 （LTB4）或IL-8的中性粒细胞趋化性降低。在对照组和患者的中性粒细胞中检测到IL-8受体CXCR1的转录或表达没有差异。然而，败血性中性粒细胞在IL-8或LTB4的作用下未能增加酪氨酸磷酸化和肌动蛋白聚合。相比之下，脓毒性中性粒细胞，与对照组相似，表现出吞噬活性，诱导肌动蛋白聚合和增加磷酸酪氨酸含量。用细胞因子和脂多糖（LPS）模拟内源性脓毒环境，抑制肌动蛋白聚合和酪氨酸磷酸化，以响应IL-8或LTB4。G蛋白偶联受体激酶2 （GRK2）和GRK5在细胞因子加LPS处理的脓毒症中性粒细胞和对照细胞中高表达。数据表明，脓毒症期间产生的内源性介质可能持续激活循环中性粒细胞，导致GRK激活，从而诱导中性粒细胞对化学引诱剂脱敏。
The deregulation of inflammatory response during sepsis seems to reflect the overproduction of mediators, which suppress leukocyte functions. We investigated the intracellular mechanisms underlying the inability of neutrophils from severe septic patients to migrate toward chemoattractants. Patients with sepsis (52) and 15 volunteers were prospectively enrolled. Patients presented increased circulating levels of tumor necrosis factor-a, interferon-gamma, interleukin (IL)-8, and IL-10. Patients showed reduced neutro-Phil chemotaxis to formyl-methionyl-leucyl-phenylaianine (FMLP), leukotriene B-4 (LTB4) or IL-8. No difference in the transcription or expression of the IL-8 receptor, CXCR1, was detected in neutrophils from controls and patients. However, septic neutrophils failed to increase tyrosine phosphorylation and actin polymerization in response to IL-8 or LTB4. In contrast, septic neutrophils, similar to controls, showed phagocytic activity that induced actin polymerization and augmented phosphotyrosine content. Treatment of control neutrophils with cytokines and lipopolysaccharlde (LPS) to mimic endogenous septic environment inhibited actin polymerization and tyrosine phosphorylation in response to IL-8 or LTB4. High expression of G protein-coupled receptor kinase 2 (GRK2) and GRK5 was detected in septic neutrophils and control cells treated with cytokines plus LPS. Data suggest that endogenous mediators produced during sepsis might continually activate circulating neutrophils, leading to GRK activation, which may induce neutrophil desensitization to chemoattractants.