C5a Receptor Mediates Neutrophil Activation and ANCA-Induced Glomerulonephritis
C5a Receptor Mediates Neutrophil Activation and ANCA-Induced Glomerulonephritis
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DOI：
10.1681/asn.2008050497
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发表时间：
2009-02-01
影响因子：
13.6
通讯作者：
Kettritz, Ralph
中科院分区：
文献类型：
--
作者：
Schreiber, Adrian;Xiao, Hong;Kettritz, Ralph
抗中性粒细胞胞浆抗体（ANCA）诱导的坏死性新月体肾小球肾炎（NCGN）的发病机制需要补体的参与。我们检验了过敏毒素C5 a通过中性粒细胞C5 a受体（C5 aR）对疾病诱导起关键作用的假设。来自ANICA激活的中性粒细胞的上清液激活正常血清中的补体级联反应，产生C5 a。这种条件血清引发中性粒细胞ANCA诱导的呼吸爆发;中性粒细胞C5 aR阻断废除这种引发，但C3 aR阻断没有。此外，重组C5 a而非C3 a剂量依赖性地引发中性粒细胞进行ANCA诱导的呼吸爆发。为了测试C5 aR在NCGN模型中的作用，我们用髓过氧化物酶免疫髓过氧化物酶缺陷小鼠，照射它们，并将野生型小鼠或C5 aR缺陷小鼠的骨髓移植到它们中。所有接受野生型骨髓的小鼠（6/6），但接受C5 aR缺陷型骨髓的8只小鼠中只有1只发生NCGN（P < 0.05）。接受C5 aR缺陷骨髓的小鼠的白蛋白尿和中性粒细胞向肾小球的内流也显著减少（P < 0.05）。总之，C5 a和中性粒细胞C5 aR可能构成ANCA介导的中性粒细胞活化的放大环。C5 aR可能为ANCA诱导的坏死性新月体肾炎提供新的治疗靶点。
Anti-neutrophil cytoplasmic autoantibody (ANCA)-induced necrotizing crescentic glomerulonephritis (NCGN) requires complement participation in its pathogenesis. We tested the hypothesis that the anaphylatoxin C5a is pivotal to disease induction via the neutrophil C5a receptor (C5aR). Supernatants from ANICA-activated neutrophils activated the complement cascade in normal serum, producing C5a. This conditioned serum primed neutrophils for ANCA-induced respiratory burst; neutrophil C5aR blockade abrogated this priming, but C3aR blockade did not. Furthermore, recombinant C5a but not C3a dosage-dependently primed neutrophils for ANCA-induced respiratory burst. To test the role of C5aR in a model of NCGN, we immunized myeloperoxidase-deficient mice with myeloperoxidase, irradiated them, and transplanted bone marrow from wild-type mice or C5aR-deficient mice into them. All mice that received wild-type marrow (six of six) but only one of eight mice that received C5aR-deficient marrow developed NCGN (P < 0.05). Albuminuria and neutrophil influx into glomeruli were also significantly attenuated in the mice that received C5aR-deficient marrow (P < 0.05). In summary, C5a and the neutrophil C5aR may compose an amplification loop for ANCA-mediated neutrophil activation. The C5aR may provide a new therapeutic target for ANCA-induced necrotizing crescentic glomerulonephritis.