ANKRD22 aggravates sepsis-induced ARDS and promotes pulmonary M1 macrophage polarization

IF 4.7 Q2 IMMUNOLOGY Journal of Translational Autoimmunity Pub Date : 2023-12-21 DOI:10.1016/j.jtauto.2023.100228
Shi Zhang , Yao Liu , Xiao-Long Zhang , Yun Sun , Zhong-Hua Lu
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Abstract

Acute respiratory distress syndrome (ARDS) is independently associated with a poor prognosis in patients with sepsis. Macrophage M1 polarization plays an instrumental role in this process. Therefore, the exploration of key molecules affecting acute lung injury and macrophage M1 polarization may provide therapeutic targets for the treatment of septic ARDS. Here, we identified that elevated levels of Ankyrin repeat domain-containing protein 22 (ANKRD22) were associated with poor prognosis and more pronounced M1 macrophage polarization in septic patients by analyzing high-throughput data. ANKRD22 expression was also significantly upregulated in the alveolar lavage fluid, peripheral blood, and lung tissue of septic ARDS model mice. Knockdown of ANKRD22 significantly attenuated acute lung injury in mice with sepsis-induced ARDS and reduced the M1 polarization of lung macrophages. Furthermore, deletion of ANKRD22 in macrophages inhibited M1 macrophage polarization and reduced levels of phosphorylated IRF3 and intracellular interferon regulatory factor 3 (IRF3) expression, while re-expression of ANKRD22 reversed these changes. Further experiments revealed that ANKRD22 promotes IRF3 activation by binding to mitochondrial antiviral-signaling protein (MAVS). In conclusion, these findings suggest that ANKRD22 promotes the M1 polarization of lung macrophages and exacerbates sepsis-induced ARDS.

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ANKRD22 会加重败血症诱导的 ARDS 并促进肺 M1 巨噬细胞极化
急性呼吸窘迫综合征(ARDS)与败血症患者的不良预后密切相关。巨噬细胞 M1 极化在这一过程中起着重要作用。因此,探索影响急性肺损伤和巨噬细胞 M1 极化的关键分子可能为治疗脓毒症 ARDS 提供治疗靶点。在这里,我们通过分析高通量数据发现,脓毒症患者体内含Ankyrin重复结构域蛋白22(ANKRD22)水平的升高与不良预后和更明显的巨噬细胞M1极化有关。在脓毒症 ARDS 模型小鼠的肺泡灌洗液、外周血和肺组织中,ANKRD22 的表达也明显上调。敲除ANKRD22能显著减轻脓毒症诱导的ARDS小鼠的急性肺损伤,并减少肺巨噬细胞的M1极化。此外,在巨噬细胞中删除ANKRD22可抑制巨噬细胞的M1极化,降低磷酸化IRF3的水平和细胞内干扰素调节因子3(IRF3)的表达,而重新表达ANKRD22可逆转这些变化。进一步的实验发现,ANKRD22通过与线粒体抗病毒信号蛋白(MAVS)结合来促进IRF3的激活。总之,这些研究结果表明,ANKRD22能促进肺巨噬细胞的M1极化,并加剧败血症诱发的ARDS。
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来源期刊
Journal of Translational Autoimmunity
Journal of Translational Autoimmunity Medicine-Immunology and Allergy
CiteScore
7.80
自引率
2.60%
发文量
33
审稿时长
55 days
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