Li Ning, Liu Bohao, He Ruyuan, Li Guorui, Xiong Rui, Fu Tinglv, Li Donghang, Xu Chenzhen, Wang Bo, Geng Qing
Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun 130021, China.
iScience. 2023 Jun 19;26(7):107158. doi: 10.1016/j.isci.2023.107158. eCollection 2023 Jul 21.
Activated inflammation and pyroptosis in macrophage are closely associated with acute lung injury (ALI). Histone deacetylase 3 (HDAC3) serves as an important enzyme that could repress gene expression by mediating chromatin remodeling. In this study, we found that HDAC3 was highly expressed in lung tissues of lipopolysaccharide (LPS)-treated mice. Lung tissues from macrophage HDAC3-deficient mice stimulated with LPS showed alleviative lung pathological injury and inflammatory response. HDAC3 silencing significantly blocked the activation of cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway in LPS-induced macrophage. LPS could recruit HDAC3 and H3K9Ac to the miR-4767 gene promoter, which repressed the expression of miR-4767 to promote the expression of cGAS. Taken together, our findings demonstrated that HDAC3 played a pivotal role in mediating pyroptosis in macrophage and ALI by activating cGAS/STING pathway through its histone deacetylation function. Targeting HDAC3 in macrophage may provide a new therapeutic target for the prevention of LPS-induced ALI.
巨噬细胞中激活的炎症和焦亡与急性肺损伤（ALI）密切相关。组蛋白去乙酰化酶3（HDAC3）是一种重要的酶，可通过介导染色质重塑来抑制基因表达。在本研究中，我们发现HDAC3在脂多糖（LPS）处理的小鼠肺组织中高表达。用LPS刺激巨噬细胞HDAC3缺陷小鼠的肺组织，显示出减轻的肺病理损伤和炎症反应。HDAC3沉默显著阻断了LPS诱导的巨噬细胞中环磷酸鸟苷-腺苷酸合成酶（cGAS）/干扰素基因刺激因子（STING）途径的激活。LPS可将HDAC3和H3K9Ac募集到miR-4767基因启动子上，抑制miR-4767的表达以促进cGAS的表达。综上所述，我们的研究结果表明，HDAC3通过其组蛋白去乙酰化功能激活cGAS/STING途径，在介导巨噬细胞焦亡和ALI中起关键作用。靶向巨噬细胞中的HDAC3可能为预防LPS诱导的ALI提供新的治疗靶点。
