C5a anaphylatoxin is a major regulator of activating versus inhibitory FcγRs in immune complex-induced lung disease
C5a anaphylatoxin is a major regulator of activating versus inhibitory FcγRs in immune complex-induced lung disease
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DOI：
10.1172/jci200216577
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发表时间：
2002-12-01
影响因子：
15.9
通讯作者：
Gessner, JE
中科院分区：
文献类型：
--
作者：
Shushakova, N;Skokowa, J;Gessner, JE
IgG Fc受体（Fc γ R，特别是Fc γ RIII）和补体（特别是C5 a过敏毒素）是对免疫复合物（IC）的急性炎症反应的关键效应物。然而，这两个关键组分是否以及如何在体内相互作用尚不清楚。我们在这里使用小鼠模型的急性肺IC超敏反应，以分析其潜在的相互作用。Fc γ RIII和C5 aR在肺泡巨噬细胞（AM）上共表达，并且Fc γ RIII和C5 aR突变小鼠均显示免疫应答受损。我们发现，重组人C5 a（rhC 5a）可以控制各种Fc γ R的反向表达，与rhC 5a的共刺激IC的结果在体外和体内强烈增强Fc γ RIII触发的细胞活化。此外，我们在这里表明，早期IC诱导的生物活性C5 a，其与C5 aR的相互作用，导致诱导激活FcgammaRIII和抑制FcgammaRII对AM的有效细胞因子的产生和肺病理中性粒细胞的招聘似乎是至关重要的。因此，C5 a是一种有效的化学引诱物，在调节抑制性/活化性Fc γ RII/III受体对以连接免疫炎症中的补体和Fc γ R效应子途径方面具有更广泛的关键功能。
IgG Fc receptors (FcgammaRs, especially FcgammaRIII) and complement (in particular, C5a anaphylatoxin) are critical effectors of the acute inflammatory response to immune complexes (ICs). However, it is unknown whether and how these two key components can interact with each other in vivo. We use here a mouse model of the acute pulmonary IC hypersensitivity reaction to analyze their potential interaction. FcgammaRIII and C5aR are coexpressed on alveolar macrophages (AMs), and both FcgammaRIII and C5aR mutant mice display impaired immune responses. We find that recombinant human C5a (rhC5a) can control inverse expression of various FcgammaRs, and costimulation of ICs with rhC5a results in strong enhancement of FcgammaRIII-triggered cellular activation in vitro and in vivo. Moreover, we show here that early IC-induced bioactive C5a, and its interaction with C5aR, causes induction of activating FcgammaRIII and suppression of inhibitory FcgammaRII on AMs that appears crucial for efficient cytokine production and neutrophil recruitment in lung pathology. Therefore, C5a, which is a potent chemoattractant, has a broader critical function in regulating the inhibitory/activating FcgammaRII/III receptor pair to connect complement and FcgammaR effector pathways in immune inflammation.