C5a Receptor Enables Participation of Mast Cells in Immune Complex Arthritis Independently of Fcγ Receptor Modulation
C5a Receptor Enables Participation of Mast Cells in Immune Complex Arthritis Independently of Fcγ Receptor Modulation
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DOI：
10.1002/art.27659
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发表时间：
2010-11-01
影响因子：
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通讯作者：
Lee, David M.
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文献类型：
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作者：
Nigrovic, Peter A.;Malbec, Odile;Lee, David M.
Objective.肥大细胞是组织驻留的免疫哨兵，参与炎症性关节疾病的发病机制。本研究的目的是验证我们的假设，即补体片段可能是自身免疫性关节炎滑膜肥大细胞的关键激活剂。体内研究使用鼠K/BxN关节炎模型，这是一种由IgG免疫复合物介导的远端对称性多关节炎。通过免疫组化和功能研究确定滑膜肥大细胞上C5 aR的表达。将C5 aR（-/-）和对照肥大细胞移植到肥大细胞缺陷型WBB 6 F1-Kit（w）/Kit（W-v）（W/Wv）小鼠中，以检查关节炎对该受体的需求。在C5 aR（-/-）动物以及小鼠和人肥大细胞培养物中研究了肥大细胞的C5 aR依赖性激活。结果。小鼠滑膜肥大细胞表达功能性C5 aR。与它们的野生型对应物不同，过继转移到W/Wv小鼠中的C5 aR（-/-）肥大细胞不能恢复关节炎，尽管滑膜移植相当。在体内K/BxN血清对C5 aR（-/-）肥大细胞的激活保持完整，表明C5 aR对于正常IgG介导的触发是无效的。与该结果一致，用C5 a处理的培养的肥大细胞不能调节Fc γ受体（Fc γ R）的表达或以其他方式改变活化阈值。在人肥大细胞中，C5 a促进了中性粒细胞趋化因子白细胞介素-8的产生，并且在C5 aR（-/-）小鼠中，血清给药后24小时中性粒细胞的募集受损，这表明增强的中性粒细胞趋化因子产生是关节炎中肥大细胞对C5 aR的需求的基础。在免疫复合物关节炎中，需要通过C5 aR刺激来释放滑膜肥大细胞的促炎活性，尽管其机制与C5 a调节的Fc γ R表达不同。
Objective. Mast cells are tissue-resident immune sentinels that are implicated in the pathogenesis of inflammatory joint disease. The aim of this study was to test our hypothesis that complement fragments could be key activators of synovial mast cells in autoimmune arthritis.Methods. In vivo studies used the murine K/BxN arthritis model, a distal symmetric polyarthritis mediated by IgG immune complexes. Expression of C5aR on synovial mast cells was determined by immunohistochemical and functional studies. C5aR(-/-) and control mast cells were engrafted into mast cell-deficient WBB6 F1-Kit(w)/Kit(W-v) (W/Wv) mice to examine the requirement for this receptor in arthritis. C5aR-dependent activation of mast cells was investigated in C5aR(-/-) animals and in murine and human mast cell cultures.Results. Murine synovial mast cells express functional C5aR. Unlike their wild-type counterparts, C5aR(-/-) mast cells adoptively transferred into W/Wv mice were not competent to restore arthritis, despite equivalent synovial engraftment. Activation of C5aR(-/-) mast cells by K/BxN serum in vivo remained intact, indicating that C5aR is dispensable for normal IgG-mediated triggering. Consistent with this result, cultured mast cells treated with C5a failed to modulate the expression of Fc gamma receptors (Fc gamma R) or to otherwise alter the activation threshold. In human mast cells, C5a promoted the production of the neutrophil chemotaxin interleukin-8, and recruitment of neutrophils at 24 hours after serum administration was impaired in C5aR(-/-) mice, suggesting that enhanced neutrophil chemoattractant production underlies the requirement for C5aR on mast cells in arthritis.Conclusion. Stimulation via C5aR is required to unleash the proinflammatory activity of synovial mast cells in immune complex arthritis, albeit via a mechanism that is distinct from C5a-modulated expression of Fc gamma R.