Frontline Science: The expression of integrin αDβ2 (CD11d/CD18) on neutrophils orchestrates the defense mechanism against endotoxemia and sepsis,Journal of Leukocyte Biology

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Frontline Science: The expression of integrin αDβ2 (CD11d/CD18) on neutrophils orchestrates the defense mechanism against endotoxemia and sepsis
Journal of Leukocyte Biology ( IF 3.6 ) Pub Date : 2021-01-13 , DOI: 10.1002/jlb.3hi0820-529rr
William P Bailey ₁ , Kui Cui ₁ , Christopher L Ardell ₁ , Kasey R Keever ₁ , Sanjay Singh ₁ , Diego J Rodriguez-Gil ₁ , Tammy R Ozment _{2,

3} , David L Williams _{2,

3} , Valentin P Yakubenko _{1,

3}

Affiliation

Neutrophil‐macrophage interplay is a fine‐tuning mechanism that regulates the innate immune response during infection and inflammation. Cell surface receptors play an essential role in neutrophil and macrophage functions. The same receptor can provide different outcomes within diverse leukocyte subsets in different inflammatory conditions. Understanding the variety of responses mediated by one receptor is critical for the development of anti‐inflammatory treatments. In this study, we evaluated the role of a leukocyte adhesive receptor, integrin α_Dβ₂, in the development of acute inflammation. α_Dβ₂ is mostly expressed on macrophages and contributes to the development of chronic inflammation. In contrast, we found that α_D‐knockout dramatically increases mortality in the cecal ligation and puncture sepsis model and LPS‐induced endotoxemia. This pathologic outcome of α_D‐deficient mice is associated with a reduced number of monocyte‐derived macrophages and an increased number of neutrophils in their lungs. However, the tracking of adoptively transferred fluorescently labeled wild‐type (WT) and α_D^−/− monocytes in WT mice during endotoxemia demonstrated only a moderate difference between the recruitment of these two subsets. Moreover, the rescue experiment, using i.v. injection of WT monocytes to α_D‐deficient mice followed by LPS challenge, showed only slightly reduced mortality. Surprisingly, the injection of WT neutrophils to the bloodstream of α_D^−/− mice markedly increased migration of monocyte‐derived macrophage to lungs and dramatically improves survival. α_D‐deficient neutrophils demonstrate increased necrosis/pyroptosis. α_Dβ₂‐mediated macrophage accumulation in the lungs promotes efferocytosis that reduced mortality. Hence, integrin α_Dβ₂ implements a complex defense mechanism during endotoxemia, which is mediated by macrophages via a neutrophil‐dependent pathway.

中文翻译：

前沿科学：中性粒细胞上整合素αDβ2（CD11d/CD18）的表达协调了针对内毒素血症和脓毒症的防御机制

中性粒细胞-巨噬细胞相互作用是一种微调机制，可调节感染和炎症期间的先天免疫反应。细胞表面受体在中性粒细胞和巨噬细胞功能中发挥重要作用。在不同的炎症条件下，相同的受体可以在不同的白细胞亚群中提供不同的结果。了解一种受体介导的多种反应对于抗炎治疗的发展至关重要。在这项研究中，我们评估了白细胞粘附受体整合素 α _D β ₂在急性炎症发展中的作用。 α _D β ₂主要在巨噬细胞上表达，有助于慢性炎症的发展。相比之下，我们发现 α _D敲除会显着增加盲肠结扎和穿刺脓毒症模型以及 LPS 诱导的内毒素血症的死亡率。 _αD缺陷小鼠的这种病理结果与其肺部单核细胞来源的巨噬细胞数量减少和中性粒细胞数量增加有关。然而，在内毒素血症期间对 WT 小鼠中过继转移的荧光标记野生型 (WT) 和 α _D ^-/−单核细胞的跟踪表明，这两个子集的募集之间仅存在中等差异。此外，救援实验向_αD缺陷小鼠静脉注射WT单核细胞，然后进行LPS攻击，结果显示死亡率仅略有降低。令人惊讶的是，将 WT 中性粒细胞注射到 α _D ^−/−小鼠的血流中显着增加了单核细胞来源的巨噬细胞向肺部的迁移，并显着提高了存活率。 α _D缺乏的中性粒细胞表现出坏死/细胞焦亡增加。 α _D β ₂介导的巨噬细胞在肺部积聚促进胞吞作用，从而降低死亡率。因此，整合素 α _D β ₂在内毒素血症期间实现了复杂的防御机制，该机制由巨噬细胞通过中性粒细胞依赖性途径介导。

更新日期：2021-01-13

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