Division of Allergic Diseases, Department of Medicine and Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
J Immunol. 2010 Jun 1;184(11):6350-8. doi: 10.4049/jimmunol.0902673. Epub 2010 May 5.
Eosinophils are multifunctional leukocytes involved in various inflammatory processes, as well as tissue remodeling and immunoregulation. During inflammation and infection, injured cells and damaged tissues release uric acid and monosodium urate (MSU) crystals as important endogenous danger signals. Uric acid is also implicated in the immunogenic effects of an authentic Th2 adjuvant, aluminum hydroxide. Eosinophils often localize at sites of Th2-type chronic inflammation; therefore, we hypothesized that eosinophils may react to endogenous danger signals. We found that human eosinophils migrate toward soluble uric acid and MSU crystals in a gradient-dependent manner. Eosinophils incubated with MSU crystals, but not those incubated with uric acid solution, produced elevated levels of IL-6 and IL-8/CXCL8. Other cytokines and chemokines, including IL-1beta, IL-10, IL-17, IFN-gamma, CCL2, CCL3, CCL4, TNF-alpha, G-CSF, GM-CSF, fibroblast growth factor, vascular endothelial growth factor, and TGF-beta, were also produced by eosinophils incubated with MSU crystals. Eosinophils exposed to MSU crystals rapidly (i.e., within 1 min of exposure) released ATP into the extracellular milieu. Importantly, this autocrine ATP was necessary for eosinophils to produce cytokines in response to MSU crystals, and P2 nucleotide receptors, in particular P2Y(2), are likely involved in this positive feedback loop. Finally, at higher concentrations, MSU crystals promoted P2R-dependent release of a granule protein (eosinophil-derived neurotoxin) and cell death. Thus, human eosinophils may respond to particulate damage-associated endogenous danger signals. These responses by eosinophils to tissue damage may explain the self-perpetuating nature of chronic inflammation in certain human diseases, such as asthma.
嗜酸性粒细胞是多功能白细胞，参与各种炎症过程以及组织重塑和免疫调节。在炎症和感染期间，受伤的细胞和受损组织释放尿酸和单钠尿酸盐（MSU）晶体作为重要的内源性危险信号。尿酸也与真正的 Th2 佐剂氢氧化铝的免疫原性作用有关。嗜酸性粒细胞通常定位于 Th2 型慢性炎症部位；因此，我们假设嗜酸性粒细胞可能对内源性危险信号作出反应。我们发现，人嗜酸性粒细胞以依赖浓度梯度的方式向可溶性尿酸和 MSU 晶体迁移。与尿酸溶液孵育的嗜酸性粒细胞而不是与 MSU 晶体孵育的嗜酸性粒细胞产生更高水平的 IL-6 和 IL-8/CXCL8。其他细胞因子和趋化因子，包括 IL-1β、IL-10、IL-17、IFN-γ、CCL2、CCL3、CCL4、TNF-α、G-CSF、GM-CSF、成纤维细胞生长因子、血管内皮生长因子和 TGF-β，也由与 MSU 晶体孵育的嗜酸性粒细胞产生。暴露于 MSU 晶体的嗜酸性粒细胞迅速（即在暴露后 1 分钟内）将 ATP 释放到细胞外环境中。重要的是，这种自分泌的 ATP 对于嗜酸性粒细胞响应 MSU 晶体产生细胞因子是必需的，并且 P2 核苷酸受体，特别是 P2Y(2)，可能参与此正反馈环。最后，在较高浓度下，MSU 晶体促进 P2R 依赖性释放颗粒蛋白（嗜酸性粒细胞衍生的神经毒素）和细胞死亡。因此，人嗜酸性粒细胞可能对颗粒状损伤相关内源性危险信号作出反应。这些嗜酸性粒细胞对组织损伤的反应可能解释了某些人类疾病（如哮喘）中慢性炎症的自我延续性质。
