Complement alternative pathway acts as a positive feedback amplification of neutrophil activation
Complement alternative pathway acts as a positive feedback amplification of neutrophil activation
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DOI：
10.1182/blood-2010-05-283564
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发表时间：
2011-01-27
期刊：
影响因子：
20.3
通讯作者：
Halbwachs-Mecarelli, Lise
中科院分区：
文献类型：
--
作者：
Camous, Laurent;Roumenina, Lubka;Halbwachs-Mecarelli, Lise
补体旁路途径在嗜中性粒细胞介导的疾病中起着重要的作用，但尚未明确理解。我们在这里表明，中性粒细胞本身激活补体时，刺激细胞因子或凝血衍生因子。在全血中，肿瘤坏死因子/甲酰-甲硫氨酰-亮氨酰-苯丙氨酸或佛波酯肉豆蔻酸酯导致C3片段结合中性粒细胞和单核细胞，但不结合T细胞。中性粒细胞，肿瘤坏死因子刺激，触发其表面上的替代途径在正常和C2-耗尽，但不是在因子B-耗尽的血清和与纯化的C3，因子B和D孵育。这独立于中性粒细胞蛋白酶、氧化剂或细胞凋亡发生。中性粒细胞分泌备解素检测到的细胞表面上，并可以集中在“原位”的替代途径激活。重要的是，补体反过来导致中性粒细胞的进一步活化，增强CD 11b表达和氧化爆发。补体诱导的中性粒细胞活化主要涉及C5 a和可能的C5 b-9复合物，在肿瘤坏死因子和血清活化的中性粒细胞上检测到。总之，中性粒细胞刺激细胞因子的结果在一个不寻常的激活自体补体的健康细胞。这触发了生理性先天免疫中的新的放大环：中性粒细胞激活替代补体途径并释放C5片段，其进一步放大中性粒细胞促炎反应。这种机制，可能需要有效的主机防御，可能是相关的补体参与嗜中性粒细胞介导的疾病。（血。2011; 117（4）：1340-1349）
Complement alternative pathway plays an important, but not clearly understood, role in neutrophil-mediated diseases. We here show that neutrophils themselves activate complement when stimulated by cytokines or coagulation-derived factors. In whole blood, tumor necrosis factor/formyl-methionyl-leucyl-phenylalanine or phorbol myristate acetate resulted in C3 fragments binding on neutrophils and monocytes, but not on T cells. Neutrophils, stimulated by tumor necrosis factor, triggered the alternative pathway on their surface in normal and C2-depleted, but not in factor B-depleted serum and on incubation with purified C3, factors B and D. This occurred independently of neutrophil proteases, oxidants, or apoptosis. Neutrophil-secreted properdin was detected on the cell surface and could focus "in situ" the alternative pathway activation. Importantly, complement, in turn, led to further activation of neutrophils, with enhanced CD11b expression and oxidative burst. Complement-induced neutrophil activation involved mostly C5a and possibly C5b-9 complexes, detected on tumor necrosis factor- and serum-activated neutrophils. In conclusion, neutrophil stimulation by cytokines results in an unusual activation of autologous complement by healthy cells. This triggers a new amplification loop in physiologic innate immunity: Neutrophils activate the alternative complement pathway and release C5 fragments, which further amplify neutrophil proinflammatory responses. This mechanism, possibly required for effective host defense, may be relevant to complement involvement in neutrophil-mediated diseases. (Blood. 2011; 117(4): 1340-1349)