Robust inflammatory responses are critical to survival following respiratory infection, with current attention focused on the clinical consequences of the Coronavirus pandemic. Epigenetic factors are increasingly recognized as important determinants of immune responses, and EZH2 is a prominent target due to the availability of highly specific and efficacious antagonists. However, very little is known about the role of EZH2 in the myeloid lineage. Here, we show EZH2 acts in macrophages to limit inflammatory responses to activation, and in neutrophils for chemotaxis. Selective genetic deletion in macrophages results in a remarkable gain in protection from infection with the prevalent lung pathogen, pneumococcus. In contrast, neutrophils lacking EZH2 showed impaired mobility in response to chemotactic signals, and resulted in increased susceptibility to pneumococcus. In summary, EZH2 shows complex, and divergent roles in different myeloid lineages, likely contributing to the earlier conflicting reports. Compounds targeting EZH2 are likely to impair mucosal immunity; however, they may prove useful for conditions driven by pulmonary neutrophil influx, such as adult respiratory distress syndrome.

中文翻译：

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组蛋白甲基转移酶 Ezh2 抑制巨噬细胞炎症反应

强烈的炎症反应对于呼吸道感染后的生存至关重要，目前的注意力集中在冠状病毒大流行的临床后果上。表观遗传因素越来越被认为是免疫反应的重要决定因素，而 EZH2 由于高度特异性和有效的拮抗剂的可用性而成为一个重要的靶点。然而，人们对 EZH2 在骨髓谱系中的作用知之甚少。在这里，我们展示了 EZH2 在巨噬细胞中发挥作用，限制炎症反应的激活，并在中性粒细胞中发挥趋化作用。巨噬细胞中的选择性基因删除可以显着提高对流行的肺部病原体肺炎球菌感染的保护。相反，缺乏 EZH2 的中性粒细胞对趋化信号的反应能力受损，并导致对肺炎球菌的易感性增加。总之，EZH2 在不同的骨髓谱系中表现出复杂且不同的作用，这可能导致了早期相互矛盾的报道。针对 EZH2 的化合物可能会损害粘膜免疫；然而，它们可能对由肺部中性粒细胞流入引起的疾病有用，例如成人呼吸窘迫综合征。