PDF(Pubmed)
Abstract：
BACKGROUND: Aberrant activation of macrophages is associated with pathogenesis of acute lung injury (ALI). However, the potential pathogenesis has not been explored.
OBJECTIVE: We aimed to identify whether histone deacetylase (HDAC) 10 is involved in lipopolysaccharide (LPS)-exposed ALI and reveal the underlying pathogenesis by which it promotes lung inflammation in LPS-exposed ALI via modifying P62 with deacetylation.
METHODS: We constructed an ALI mice model stimulated with LPS to determine the positive effect of Hdac10 deficiency. Moreover, we cultured murine alveolar macrophage cell line (MH-S cells) and primary bone marrow-derived macrophages (BMDMs) to explore the pro-inflammatory activity and mechanism of HDAC10 after LPS challenge.
RESULTS: HDAC10 expression was increased both in mice lung tissues and macrophage cell lines and promoted inflammatory cytokines production exposed to LPS. Hdac10 deficiency inhibited autophagy and inflammatory response after LPS stimulation. In vivo, Hdac10fl/fl-LysMCre mice considerably attenuated lung inflammation and inflammatory cytokines release exposed to LPS. Mechanistically, HDAC10 interacts with P62 and mediates P62 deacetylation at lysine 165 (K165), by which it promotes P62 expression and increases inflammatory cytokines production. Importantly, we identified that Salvianolic acid B (SAB), an HDAC10 inhibitor, reduces lung inflammatory response in LPS-stimulated ALI.
CONCLUSIONS: These results uncover a previously unknown role for HDAC10 in regulating P62 deacetylation and aggravating lung inflammation in LPS-induced ALI, implicating that targeting HDAC10 is an effective therapy for LPS-exposed ALI.
OBJECTIVE: We aimed to identify whether histone deacetylase (HDAC) 10 is involved in lipopolysaccharide (LPS)-exposed ALI and reveal the underlying pathogenesis by which it promotes lung inflammation in LPS-exposed ALI via modifying P62 with deacetylation.
METHODS: We constructed an ALI mice model stimulated with LPS to determine the positive effect of Hdac10 deficiency. Moreover, we cultured murine alveolar macrophage cell line (MH-S cells) and primary bone marrow-derived macrophages (BMDMs) to explore the pro-inflammatory activity and mechanism of HDAC10 after LPS challenge.
RESULTS: HDAC10 expression was increased both in mice lung tissues and macrophage cell lines and promoted inflammatory cytokines production exposed to LPS. Hdac10 deficiency inhibited autophagy and inflammatory response after LPS stimulation. In vivo, Hdac10fl/fl-LysMCre mice considerably attenuated lung inflammation and inflammatory cytokines release exposed to LPS. Mechanistically, HDAC10 interacts with P62 and mediates P62 deacetylation at lysine 165 (K165), by which it promotes P62 expression and increases inflammatory cytokines production. Importantly, we identified that Salvianolic acid B (SAB), an HDAC10 inhibitor, reduces lung inflammatory response in LPS-stimulated ALI.
CONCLUSIONS: These results uncover a previously unknown role for HDAC10 in regulating P62 deacetylation and aggravating lung inflammation in LPS-induced ALI, implicating that targeting HDAC10 is an effective therapy for LPS-exposed ALI.
摘要：
背景：巨噬细胞的异常激活与急性肺损伤（ALI）的发病机制有关。然而,潜在的发病机制尚未被探索。
目的：我们旨在确定组蛋白脱乙酰酶（HDAC）10是否与脂多糖（LPS）暴露的ALI有关，并揭示其通过修饰P62去乙酰化促进LPS暴露的ALI中肺部炎症的潜在发病机制。
方法：我们构建了用LPS刺激的ALI小鼠模型，以确定Hdac10缺乏的积极作用。此外，我们培养小鼠肺泡巨噬细胞系（MH-S细胞）和原代骨髓源性巨噬细胞（BMDMs），以探讨LPS攻击后HDAC10的促炎活性和机制。
结果：HDAC10在小鼠肺组织和巨噬细胞系中的表达增加，并促进暴露于LPS的炎性细胞因子的产生。Hdac10缺乏抑制LPS刺激后的自噬和炎症反应。在体内,Hdac10fl/fl-LysMCre小鼠显著减弱暴露于LPS的肺部炎症和炎性细胞因子释放。机械上,HDAC10与P62相互作用，并在赖氨酸165（K165）处介导P62脱乙酰，通过它促进P62表达并增加炎性细胞因子的产生。重要的是,我们确定丹酚酸B（SAB），HDAC10抑制剂，减少LPS刺激的ALI中的肺部炎症反应。
结论：这些结果揭示了HDAC10在调节LPS诱导的ALI中P62去乙酰化和加重肺部炎症中的作用，暗示靶向HDAC10是LPS暴露的ALI的有效疗法。
目的：我们旨在确定组蛋白脱乙酰酶（HDAC）10是否与脂多糖（LPS）暴露的ALI有关，并揭示其通过修饰P62去乙酰化促进LPS暴露的ALI中肺部炎症的潜在发病机制。
方法：我们构建了用LPS刺激的ALI小鼠模型，以确定Hdac10缺乏的积极作用。此外，我们培养小鼠肺泡巨噬细胞系（MH-S细胞）和原代骨髓源性巨噬细胞（BMDMs），以探讨LPS攻击后HDAC10的促炎活性和机制。
结果：HDAC10在小鼠肺组织和巨噬细胞系中的表达增加，并促进暴露于LPS的炎性细胞因子的产生。Hdac10缺乏抑制LPS刺激后的自噬和炎症反应。在体内,Hdac10fl/fl-LysMCre小鼠显著减弱暴露于LPS的肺部炎症和炎性细胞因子释放。机械上,HDAC10与P62相互作用，并在赖氨酸165（K165）处介导P62脱乙酰，通过它促进P62表达并增加炎性细胞因子的产生。重要的是,我们确定丹酚酸B（SAB），HDAC10抑制剂，减少LPS刺激的ALI中的肺部炎症反应。
结论：这些结果揭示了HDAC10在调节LPS诱导的ALI中P62去乙酰化和加重肺部炎症中的作用，暗示靶向HDAC10是LPS暴露的ALI的有效疗法。
