Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Int J Mol Sci. 2019 Mar 7;20(5):1167. doi: 10.3390/ijms20051167.
The Edema Toxin (ET), composed of a Protective Antigen (PA) and the Edema Factor (EF), is a cellular adenylate cyclase that alters host responses by elevating cyclic adenosine monophosphate (cAMP) to supraphysiologic levels. However, the role of ET in systemic anthrax is unclear. Efferocytosis is a cAMP-sensitive, anti-inflammatory process of apoptotic cell engulfment, the inhibition of which may promote sepsis in systemic anthrax. Here, we tested the hypothesis that ET inhibits efferocytosis by primary human macrophages and evaluated the mechanisms of altered efferocytic signaling. ET, but not PA or EF alone, inhibited the efferocytosis of early apoptotic neutrophils (PMN) by primary human M2 macrophages (polarized with IL-4, IL-10, and/or dexamethasone) at concentrations relevant to those encountered in systemic infection. ET inhibited Protein S- and MFGE8-dependent efferocytosis initiated by signaling through MerTK and αVβ5 receptors, respectively. ET inhibited Rac1 activation as well as the phosphorylation of Rac1 and key activating sites of calcium calmodulin-dependent kinases CamK1α, CamK4, and vasodilator-stimulated phosphoprotein, that were induced by the exposure of M2(Dex) macrophages to Protein S-opsonized apoptotic PMN. These results show that ET impairs macrophage efferocytosis and alters efferocytic receptor signaling.
水肿毒素（ET）由保护性抗原（PA）和水肿因子（EF）组成，是一种细胞腺苷酸环化酶，通过将环腺苷酸（cAMP）升高至超生理水平来改变宿主反应。然而，ET 在系统性炭疽病中的作用尚不清楚。吞噬作用是一种 cAMP 敏感的、抗炎的凋亡细胞吞噬过程，其抑制可能促进系统性炭疽病中的败血症。在这里，我们检验了 ET 通过原代人巨噬细胞抑制吞噬作用的假说，并评估了改变的吞噬信号转导机制。ET（而非单独的 PA 或 EF）以与全身感染中遇到的浓度相关的浓度抑制原代人 M2 巨噬细胞（通过 IL-4、IL-10 和/或地塞米松极化）吞噬早期凋亡中性粒细胞（PMN）的吞噬作用。ET 抑制由 MerTK 和 αVβ5 受体分别通过信号转导启动的蛋白 S 和 MFGE8 依赖性吞噬作用。ET 抑制 Rac1 激活以及 Rac1 和钙调蛋白依赖性激酶 CamK1α、CamK4 和血管扩张刺激磷蛋白的关键激活位点的磷酸化，这些磷酸化是 M2（Dex）巨噬细胞暴露于蛋白 S 调理的凋亡 PMN 后诱导的。这些结果表明，ET 损害巨噬细胞吞噬作用并改变吞噬受体信号转导。
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