Department of Burns and Cutaneous Surgery, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China.
Department of Burns and Cutaneous Surgery, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China.
Immunobiology. 2022 Nov;227(6):152300. doi: 10.1016/j.imbio.2022.152300. Epub 2022 Nov 1.
Dysregulated interferon regulatory factor 8 (IRF8) mediated inducible nitric oxide synthase (iNOS) transcription is crucial to the pathogenesis of several inflammatory disorders. However, the molecular mechanism that control the transcription activity of IRF8 in the regulation of iNOS is not fully elucidated. This study is undertaken to determine whether SIRT1 impacts IRF8 acetylation level in the macrophages.
The silver stain, mass spectrum, bone marrow-derived monocytes differentiation, lentiviral transduction, immunoprecipitation and chromatin immunoprecipitation assay were used to investigate the relationship between IRF8 and SIRT1.
We demonstrate that deacetylation of IRF8 is induced by lipopolysaccharide (LPS) and suppresses iNOS expression. Macrophages expressing acetylation-defective iNOS are highly septic upon transfer to macrophages cleaned up mice. Mechanistically, deacetylation IRF8 facilitates the binding of silent information regulator 1 (SIRT1) to the iNOS promoter and restricts iNOS transcription. The expression of iNOS was enhanced in the macrophages from SIRT1 conditional knockout mice and the progression of sepsis is more serious.
The discovery of the IRF8-SIRT1 interaction that governs iNOS expression may exploit new therapeutic strategies for inflammatory disorders.
干扰素调节因子 8（IRF8）介导的诱导型一氧化氮合酶（iNOS）转录失调对几种炎症性疾病的发病机制至关重要。然而，控制 IRF8 在 iNOS 调节中转录活性的分子机制尚未完全阐明。本研究旨在确定 SIRT1 是否影响巨噬细胞中 IRF8 的乙酰化水平。
使用银染、质谱、骨髓源性单核细胞分化、慢病毒转导、免疫沉淀和染色质免疫沉淀检测来研究 IRF8 和 SIRT1 之间的关系。
我们证明 LPS 诱导的 IRF8 去乙酰化抑制 iNOS 表达。转移到巨噬细胞清除小鼠的巨噬细胞中，表达乙酰化缺陷型 iNOS 的细胞极易发生败血症。从机制上讲，IRF8 的去乙酰化促进沉默信息调节因子 1（SIRT1）与 iNOS 启动子结合，并限制 iNOS 转录。SIRT1 条件性敲除小鼠的巨噬细胞中 iNOS 的表达增强，败血症的进展更为严重。
发现 IRF8-SIRT1 相互作用控制 iNOS 表达，可能为炎症性疾病的治疗提供新的策略。
