Schumacher Neele, Schmidt Stefanie, Schwarz Jeanette, Dohr Dana, Lokau Juliane, Scheller Jürgen, Garbers Christoph, Chalaris Athena, Rose-John Stefan, Rabe Björn
Institute of Biochemistry, Medical Faculty, Christian Albrechts University, 24098 Kiel, Germany; and.
Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.
J Immunol. 2016 Nov 1;197(9):3705-3715. doi: 10.4049/jimmunol.1600909. Epub 2016 Oct 3.
Neutrophil and mononuclear cell infiltration during inflammatory processes is highly regulated. The first cells at the site of infection or inflammation are neutrophils, followed by mononuclear cells. IL-6 plays an important role during inflammatory states. It has been shown in several models that the soluble form of IL-6R (sIL-6R) is involved in the recruitment of mononuclear cells by a mechanism called IL-6 trans-signaling. It had been speculated that sIL-6R was generated at the site of inflammation by shedding from neutrophils via activation of the metalloprotease ADAM17. Attempts to genetically delete the floxed ADAM17 gene selectively in myeloid cells infiltrating an air pouch cavity upon injection of carrageenan failed because in transgenic mice, LysM did not lead to appreciable loss of the ADAM17 protein in these cells. We therefore used ADAM17 hypomorphic mice, which only express ∼5% of ADAM17 wild-type levels in all tissues and show virtually no shedding of all tested ADAM17 substrates, to clarify the role of ADAM17 during local inflammation in the murine air pouch model. In the present study, we demonstrate that although IL-6 and the trans-signaling mechanism is mandatory for cellular infiltration in this model, it is not ADAM17-mediated shedding of IL-6R within the pouch that orchestrates this inflammatory process. Instead, we demonstrate that sIL-6R is infiltrating from the circulation in an ADAM17-independent process. Our data suggest that this infiltrating sIL-6R, which is needed for IL-6 trans-signaling, is involved in the controlled resolution of an acute inflammatory episode.
炎症过程中中性粒细胞和单核细胞的浸润受到高度调控。感染或炎症部位最早出现的细胞是中性粒细胞，随后是单核细胞。白细胞介素-6（IL-6）在炎症状态中发挥重要作用。在多个模型中已表明，IL-6受体的可溶性形式（sIL-6R）通过一种称为IL-6转信号传导的机制参与单核细胞的募集。据推测，sIL-6R是在炎症部位通过金属蛋白酶ADAM17激活后从中性粒细胞上脱落而产生的。在注射角叉菜胶后，试图在浸润气袋腔的髓样细胞中选择性地基因敲除floxed ADAM17基因，但未成功，因为在转基因小鼠中，LysM并未导致这些细胞中ADAM17蛋白明显缺失。因此，我们使用ADAM17低表达小鼠，其在所有组织中仅表达约5%的ADAM17野生型水平，并且几乎没有所有测试的ADAM17底物的脱落，以阐明ADAM17在小鼠气袋模型局部炎症中的作用。在本研究中，我们证明，尽管IL-6和转信号传导机制在该模型中对细胞浸润是必需的，但并非气袋内ADAM17介导的IL-6R脱落协调了这一炎症过程。相反，我们证明sIL-6R是以一种不依赖ADAM17的过程从循环中浸润进来的。我们的数据表明，这种参与IL-6转信号传导所需的浸润性sIL-6R，参与了急性炎症发作的可控消退。
