HDAC3 promotes macrophage pyroptosis via regulating histone deacetylation in acute lung injury
iScience(2023)
摘要
Abstract 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. Here, we aim to explore the role and potential molecular basis of HDAC3 in lipopolysaccharide (LPS)-induced ALI. We found that HDAC3 was highly expressed in lung tissues of LPS-treated mice and in LPS-induced macrophages. Lung tissues from macrophage HDAC3-deficient mice stimulated with LPS showed alleviative lung pathological injury and inflammatory response. HDAC3 silence by small interfering RNA (siRNA) significantly blocked the activation of cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway while HDAC3 overexpression by adenovirus transfection significantly promoted the activation of cGAS/STING pathway and aggravated pyroptosis in LPS-induced macrophage. However, HDAC3 silence or overexpression at baseline showed no effects on the level of mitochondrial DNA (mt-DNA) and the activation of cGAS/STING pathway. But HDAC3 at baseline could change the mRNA and protein levels of cGAS. Additionally, autophagy or proteasome inhibition in LPS-induced macrophages transfected with Hdac3 siRNA did not affect the protein level of cGAS. Mechanistically, cGAS was a direct target gene of miR-4767 in macrophage. LPS could recruit HDAC3 and H3K9Ac to the miR-4767 gene promoter, which repressed the expression of miR-4767 by decreasing histone acetylation of the miR-4767 gene promoter. To this end, intratracheal administration of liposomes loaded with Hdac3 siRNA prevented mice from LPS-induced lung injury and inflammation. Taken together, our findings demonstrated that HDAC3 played a pivotal role in mediating pyroptosis in macrophage and ALI by activating cGAS/STING pathway through decreasing histone acetylation of the miR-4767 gene promoter. Targeting HDAC3 in macrophage may provide a new therapeutic target for the prevention of LPS-induced ALI.
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关键词
macrophage pyroptosis,acute lung injury,histone deacetylation
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