小柯机器人

美国梅奥诊所医学院Jie Sun研究组取得最新进展。他们发现巨噬细胞炎症与自我更新的脱钩调节了宿主从呼吸道病毒感染中的恢复。2021年5月4日出版的《免疫》杂志发表了这项成果。

他们通过定义肺泡巨噬细胞（AM）中Wnt /β-catenin途径（自我更新的核心调节剂）的影响，研究了组织巨噬细胞增殖和炎症特性之间的关系。Wnt配体激活β-catenin可抑制AM增殖和干性，但可促进炎症活性。在鼠流感病毒性肺炎模型中，β-catenin介导的AM炎性活性促进了急性宿主发病。相比之下，AM增殖使病毒性清除后的补充性AM能够重新增殖并恢复组织。

从机制上讲，Wnt治疗促进了β-catenin-HIF-1α相互作用和糖酵解依赖性炎症，同时抑制了线粒体代谢，从而抑制了AM的增殖。HIF-1α的不同活性在体内可区分增生性和炎症性AM。β-catenin-HIF-1α轴在人类AMs中是保守的，并且在COVID-19患者中与巨噬细胞炎症相关的HIF-1α表达增强。因此，肺巨噬细胞的炎症和修复活性受β-catenin-HIF-1α信号传导的调节，对严重呼吸系统疾病的治疗具有重要意义。

研究人员表示，组织巨噬细胞在体内平衡过程中自我更新，并在微生物感染后产生炎性介质。

附：英文原文

Title: Uncoupling of macrophage inflammation from self-renewal modulates host recovery from respiratory viral infection

Author: Bibo Zhu, Yue Wu, Su Huang, Ruixuan Zhang, Young Min Son, Chaofan Li, In Su Cheon, Xiaochen Gao, Min Wang, Yao Chen, Xian Zhou, Quynh Nguyen, Anthony T. Phan, Supriya Behl, M. Mark Taketo, Matthias Mack, Virginia S. Shapiro, Hu Zeng, Hideki Ebihara, John J. Mullon, Eric S. Edell, Janani S. Reisenauer, Nadir Demirel, Ryan M. Kern, Rana Chakraborty, Weiguo Cui, Mark H. Kaplan, Xiaobo Zhou, Ananda W. Goldrath, Jie Sun

Issue&Volume: 2021-05-04

Abstract: Tissue macrophages self-renew during homeostasis and produce inflammatory mediatorsupon microbial infection. We examined the relationship between proliferative and inflammatoryproperties of tissue macrophages by defining the impact of the Wnt/β-catenin pathway,a central regulator of self-renewal, in alveolar macrophages (AMs) . Activation ofβ-catenin by Wnt ligand inhibited AM proliferation and stemness, but promoted inflammatoryactivity. In a murine influenza viral pneumonia model, β-catenin-mediated AM inflammatoryactivity promoted acute host morbidity; in contrast, AM proliferation enabled repopulationof reparative AMs and tissue recovery following viral clearance. Mechanistically,Wnt treatment promoted β-catenin-HIF-1α interaction and glycolysis-dependent inflammationwhile suppressing mitochondrial metabolism and thereby, AM proliferation. DifferentialHIF-1α activities distinguished proliferative and inflammatory AMs in vivo. This β-catenin-HIF-1α axis was conserved in human AMs and enhanced HIF-1α expressionassociated with macrophage inflammation in COVID-19 patients. Thus, inflammatory andreparative activities of lung macrophages are regulated by β-catenin-HIF-1α signaling,with implications for the treatment of severe respiratory diseases.

DOI: 10.1016/j.immuni.2021.04.001

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00138-2

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