G9a promotes inflammation in Streptococcus pneumoniae induced pneumonia mice by stimulating M1 macrophage polarization and H3K9me2 methylation in FOXP1 promoter region

Abstract

Background: Streptococcus pneumoniae has become a leading cause of pneumonia in recent years. Here, we investigated the mechanism of histone methylase G9a in Streptococcus pneumoniae-induced pneumonia (Spn).Methods: G9a expression in Spn mouse tissue was measured. G9a lentivirus interference vector was injected into Spn mice to evaluate the wet and dry weight of the right upper lobe and the total lung water content (TLW) and wet/dry ratio (W/D). The number of neutrophils, macrophages, and lymphocytes in bronchoalveolar lavage fluid (BALF) was detected, and the levels of interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and IL-10 in BALF were assessed. The expressions of M1 and M2 macrophage markers were also detected. The enrichment of histone 3 lysine 9 dimethylation (H3K9me2) in the Forkhead Box P1 (FOXP1) promoter was detected by chromatin immunoprecipitation (ChIP) assay, and the transcription level of FOXP1 was detected. Mouse macrophage RAW264.7 was induced by lipopolysaccharide (LPS) following G9a interference.Results: G9a in the lung tissue of Spn mice was increased. After G9a knockdown, the mouse weight increased, the infiltration of inflammatory cells was decreased, levels of pro-inflammatory cytokines in BALF were decreased, CD86 and inducible nitric oxide synthase (iNOS) were decreased, and CD206 and arginase-1 (Arg-1) were elevated. In LPS-induced RAW264.7, G9a inhibited macrophage polarization to M1 and promoted macrophage polarization to M2. G9a promoted H3K9me2 methylation in the FOXP1 promoter region and inhibited its transcription, while FOXP1 downregulation reversed the inhibition of G9a knockdown on macrophage polarization to M1 and the inflammatory effect on Spn mice.Conclusions: G9a promotes M1 polarization of macrophages by promoting H3K9me2 methylation in the FOXP1 promoter region, promoting an inflammatory response in Spn mice.

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“…LPS can activate the natural immune response and secrete a large number of inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, the contents of which in BALF directly reflect the degree of inflammatory response in the alveolar cavity [ 33 , 34 ]. In addition, current research has suggested that epithelial cells are also involved in regulating inflammation and lung defense, in which AT2 cells serve as one of the main sources of neutrophil chemokines [ 35 ].…”

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