Mitofusin-2 regulates leukocyte adhesion and β2 integrin activation,Journal of Leukocyte Biology

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Mitofusin-2 regulates leukocyte adhesion and β2 integrin activation
Journal of Leukocyte Biology ( IF 3.6 ) Pub Date : 2021-09-08 , DOI: 10.1002/jlb.1a0720-471r
Wei Liu ₁ , Alan Y Hsu ₂ , Yueyang Wang ₂ , Tao Lin ₁ , Hao Sun ₃ , Joel S Pachter ₁ , Alex Groisman ₄ , Matthew Imperioli ₅ , Fernanda Wajnsztajn Yungher ₅ , Liang Hu ₆ , Penghua Wang ₁ , Qing Deng _{2,

7,

8} , Zhichao Fan ₁

Affiliation

Neutrophils are critical for inflammation and innate immunity, and their adhesion to vascular endothelium is a crucial step in neutrophil recruitment. Mitofusin-2 (MFN2) is required for neutrophil adhesion, but molecular details are unclear. Here, we demonstrated that β₂-integrin-mediated slow-rolling and arrest, but not PSGL-1-mediated cell rolling, are defective in MFN2-deficient neutrophil-like HL60 cells. This adhesion defect is associated with reduced expression of fMLP (N-formylmethionyl-leucyl-phenylalanine) receptor FPR1 as well as the inhibited β₂ integrin activation, as assessed by conformation-specific monoclonal antibodies. MFN2 deficiency also leads to decreased actin polymerization, which is important for β2 integrin activation. Mn²⁺-induced cell spreading is also inhibited after MFN2 knockdown. MFN2 deficiency limited the maturation of β2 integrin activation during the neutrophil-directed differentiation of HL60 cells, which is indicated by CD35 and CD87 markers. MFN2 knockdown in β2-integrin activation-matured cells (CD87^high population) also inhibits integrin activation, indicating that MFN2 directly affects β2 integrin activation. Our study illustrates the function of MFN2 in leukocyte adhesion and may provide new insights into the development and treatment of MFN2 deficiency-related diseases.

中文翻译：

Mitofusin-2 调节白细胞粘附和 β2 整合素激活

中性粒细胞对炎症和先天免疫至关重要，它们与血管内皮的粘附是中性粒细胞募集的关键步骤。Mitofusin-2 (MFN2) 是中性粒细胞粘附所必需的，但分子细节尚不清楚。在这里，我们证明了 β ₂整合素介导的缓慢滚动和停滞，而不是 PSGL-1 介导的细胞滚动，在 MFN2 缺陷型嗜中性粒细胞样 HL60 细胞中是有缺陷的。这种粘附缺陷与 fMLP（N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸）受体 FPR1 的表达减少以及 β ₂整合素激活受抑制有关，如通过构象特异性单克隆抗体评估的那样。MFN2 缺陷还会导致肌动蛋白聚合减少，这对 β2 整合素激活很重要。锰²⁺- 诱导的细胞扩散在 MFN2 敲低后也受到抑制。MFN2 缺陷限制了 HL60 细胞中性粒细胞定向分化过程中 β2 整合素激活的成熟，这由 CD35 和 CD87 标记物指示。β2-整合素激活成熟细胞（CD87^高群体）中的 MFN2 敲低也抑制整合素激活，表明 MFN2 直接影响 β2 整合素激活。我们的研究阐明了 MFN2 在白细胞粘附中的功能，并可能为 MFN2 缺陷相关疾病的发展和治疗提供新的见解。

更新日期：2021-09-08

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