Interleukin-33 primes mast cells for activation by IgG immune complexes.
Interleukin-33 primes mast cells for activation by IgG immune complexes.
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DOI：
10.1371/journal.pone.0047252
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Nigrovic PA
中科院分区：
文献类型：
--
作者：
Kaieda S;Wang JX;Shnayder R;Fishgal N;Hei H;Lee RT;Stevens RL;Nigrovic PA
肥大细胞（MC）是异质性细胞，其表型受来自局部微环境的信号调节。最近的研究已经确定间充质来源的细胞因子IL-33作为MC的有效直接激活剂，以及其效应表型的调节剂，并暗示这种活性在肥大细胞的能力，以促进小鼠实验性关节炎。我们探讨了IL-33通过促进IgG免疫复合物激活滑膜MC参与小鼠K/BxN关节炎的假设。与野生型（WT）对照小鼠相比，缺乏IL-33受体ST 2的转基因动物表现出MC依赖性免疫复合物诱导的血管通透性受损（耀斑）和减弱K/BxN关节炎。尽管MC在该模型中的参与是由活化IgG受体FcγRIII介导的，但我们将骨髓来源的MC与IL-33预孵育，发现不仅直接诱导细胞因子释放，而且Fcγ RIII驱动的关键致关节炎介质（包括IL-1β和CXCL 2）的产生显著增加。这种“引发”效应与mRNA积累有关，而不是Fcγ受体表达的改变，可以通过WT而不是ST 2 −/− MC与滑膜成纤维细胞的共培养来模拟，并且可以被IL-33抗体阻断。反过来，WT而不是ST 2 −/− MCs增强了成纤维细胞IL-33的表达，形成了一个正反馈回路。总之，这些发现证实了IL-33作为IgG免疫复合物介导的炎症放大器的新作用，并确定了依赖于IL-33和ST 2的潜在MC成纤维细胞放大环。
Mast cells (MCs) are heterogeneous cells whose phenotype is modulated by signals received from the local microenvironment. Recent studies have identified the mesenchymal-derived cytokine IL-33 as a potent direct activator of MCs, as well as regulator of their effector phenotype, and have implicated this activity in the ability of mast cells to contribute to murine experimental arthritis. We explored the hypothesis that IL-33 enables participation of synovial MCs in murine K/BxN arthritis by promoting their activation by IgG immune complexes. Compared to wild-type (WT) control mice, transgenic animals lacking the IL-33 receptor ST2 exhibited impaired MC-dependent immune complex-induced vascular permeability (flare) and attenuated K/BxN arthritis. Whereas participation of MCs in this model is mediated by the activating IgG receptor FcγRIII, we pre-incubated bone marrow-derived MCs with IL-33 and found not only direct induction of cytokine release but also a marked increase in FcγRIII-driven production of critical arthritogenic mediators including IL-1β and CXCL2. This “priming” effect was associated with mRNA accumulation rather than altered expression of Fcγ receptors, could be mimicked by co-culture of WT but not ST2−/− MCs with synovial fibroblasts, and was blocked by antibodies against IL-33. In turn, WT but not ST2−/− MCs augmented fibroblast expression of IL-33, forming a positive feedback circuit. Together, these findings confirm a novel role for IL-33 as an amplifier of IgG immune complex-mediated inflammation and identify a potential MC-fibroblast amplification loop dependent on IL-33 and ST2.
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