Yousef Maali, Manuel Flores Molina, Omar Khedr, Mohamed N Abdelnabi, Jessica Dion, Ghada S Hassan, Naglaa H Shoukry
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We FACS sorted intrahepatic neutrophils at key time points and examined their transcriptional profiles using RNA-sequencing. Finally, we evaluated neutrophil protein translation, mitochondrial function and metabolism, reactive oxygen species content, and neutrophil extracellular traps generation.</p><p><strong>Results: </strong>We detected 2 temporarily distinct waves of neutrophils during (1) necroinflammation (at 24 hours after injury) and (2) late repair (at 72 hours). Early neutrophils were proinflammatory, characterized by: (1) upregulation of inflammatory cytokines, (2) activation of the noncanonical NF-κB pathway, (3) reduction of protein translation, (4) decreased oxidative phosphorylation, and (5) higher propensity to generate reactive oxygen species and neutrophil extracellular traps. In contrast, late neutrophils were prorepair and enriched in genes and pathways associated with tissue repair and angiogenesis. 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引用次数: 0
摘要
背景:中性粒细胞是急性肝损伤(ALI)期间炎症的关键介质。新的证据表明,中性粒细胞还有助于损伤的缓解和组织的修复。然而,参与这些过程的不同中性粒细胞亚群及其动力学尚未明确。在此,我们描述了 ALI 期间中性粒细胞的动力学和异质性:方法:我们使用四氯化碳 ALI 模型,利用流式细胞术、组织成像和定量 RT-PCR 来描述 ALI 伤口愈合反应的坏死炎症早期和晚期修复阶段肝内中性粒细胞的特征。我们在关键时间点对肝内中性粒细胞进行了 FACS 分选,并使用 RNA 序列分析了它们的转录谱。最后,我们评估了中性粒细胞蛋白翻译、线粒体功能和代谢、活性氧含量以及中性粒细胞胞外捕获物的生成:结果:我们在(1)坏死性炎症(损伤后 24 小时)和(2)晚期修复(72 小时)期间检测到了两波暂时不同的中性粒细胞。早期的中性粒细胞具有促炎性,其特点是(1) 炎症细胞因子上调,(2) 非经典 NF-κB 通路激活,(3) 蛋白质翻译减少,(4) 氧化磷酸化降低,(5) 更倾向于产生活性氧和中性粒细胞胞外捕获物。相比之下,晚期中性粒细胞具有促进修复的作用,并富含与组织修复和血管生成相关的基因和通路。最后,早期促炎症中性粒细胞的特征是表达 C-X-C 趋化因子受体 5 的短异构体,而晚期促修复中性粒细胞的特征是表达 C-X-C 趋化因子受体 4:本研究强调了中性粒细胞的表型和功能异质性及其在 ALI 期间炎症和组织修复中的双重作用。
Two transcriptionally and functionally distinct waves of neutrophils during mouse acute liver injury.
Background: Neutrophils are key mediators of inflammation during acute liver injury (ALI). Emerging evidence suggests that they also contribute to injury resolution and tissue repair. However, the different neutrophil subsets involved in these processes and their kinetics are undefined. Herein, we characterized neutrophil kinetics and heterogeneity during ALI.
Methods: We used the carbon tetrachloride model of ALI and employed flow cytometry, tissue imaging, and quantitative RT-PCR to characterize intrahepatic neutrophils during the necroinflammatory early and late repair phases of the wound healing response to ALI. We FACS sorted intrahepatic neutrophils at key time points and examined their transcriptional profiles using RNA-sequencing. Finally, we evaluated neutrophil protein translation, mitochondrial function and metabolism, reactive oxygen species content, and neutrophil extracellular traps generation.
Results: We detected 2 temporarily distinct waves of neutrophils during (1) necroinflammation (at 24 hours after injury) and (2) late repair (at 72 hours). Early neutrophils were proinflammatory, characterized by: (1) upregulation of inflammatory cytokines, (2) activation of the noncanonical NF-κB pathway, (3) reduction of protein translation, (4) decreased oxidative phosphorylation, and (5) higher propensity to generate reactive oxygen species and neutrophil extracellular traps. In contrast, late neutrophils were prorepair and enriched in genes and pathways associated with tissue repair and angiogenesis. Finally, early proinflammatory neutrophils were characterized by the expression of a short isoform of C-X-C chemokine receptor 5, while the late prorepair neutrophils were characterized by the expression of C-X-C chemokine receptor 4.
Conclusions: This study underscores the phenotypic and functional heterogeneity of neutrophils and their dual role in inflammation and tissue repair during ALI.
期刊介绍:
Hepatology Communications is a peer-reviewed, online-only, open access journal for fast dissemination of high quality basic, translational, and clinical research in hepatology. Hepatology Communications maintains high standard and rigorous peer review. Because of its open access nature, authors retain the copyright to their works, all articles are immediately available and free to read and share, and it is fully compliant with funder and institutional mandates. The journal is committed to fast publication and author satisfaction.