Cai Jimin,Yang Yang,Han Jiahui,Gao Yu,Li Xin,Ge Xin
Background Microglial polarization and the subsequent neuroinflammatory response and oxidative stress are contributing factors for traumatic brain injury (TBI) plus hemorrhagic shock (HS) induced brain injury. In the present work, we have explored whether Lysine (K)-specific demethylase 4 A (KDM4A) modulates microglia M1 polarization in the TBI and HS mice. Results Male C57BL/6J mice were used to investigate the microglia polarization in the TBI + HS model in vivo. Lipopolysaccharide (LPS)-induced BV2 cells were used to examine the mechanism of KDM4A in regulating microglia polarization in vitro. We found that TBI + HS resulted in neuronal loss and microglia M1 polarization in vivo, reflected by the increased level of Iba1, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, malondialdehyde (MDA) and the decreased level of reduced glutathione (GSH). Additionally, KDM4A was upregulated in response to TBI + HS and microglia were among the cell types showing the increased level of KDM4A. Similar to the results in vivo, KDM4A also highly expressed in LPS-induced BV2 cells. LPS-induced BV2 cells exhibited enhanced microglia M1 polarization, and enhanced level of pro-inflammatory cytokines, oxidative stress and reactive oxygen species (ROS), while this enhancement was abolished by the suppression of KDM4A. Conclusion Accordingly, our findings indicated that KDM4A was upregulated in response to TBI + HS and microglia were among the cell types showing the increased level of KDM4A. The important role of KDM4A in TBI + HS-induced inflammatory response and oxidative stress was at least partially realized through regulating microglia M1 polarization.
Bai Xianan,Cai Shanshan,Jiang Jie,Tian Maojin,Du Jianxin,Zhao Peiqing
Breast cancer remains a leading cause of cancer-related mortality worldwide, largely due to the persistence of an immunosuppressive tumor microenvironment that limits therapeutic efficacy. However, the molecular mechanisms underlying this immune suppression are not fully understood. Here, we identify Semaphorin 7 A (Sema7a) as a key regulator of antitumor immunity in breast cancer through its interaction with Lysine Demethylase 4 A (Kdm4a). Transcriptomic analyses of The Cancer Genome Atlas (TCGA) dataset revealed Sema7a as an immune-related hub gene using Weighted Gene Co-expression Network Analysis and Least Absolute Shrinkage and Selection Operator algorithms. Functional experiments in breast cancer cell lines demonstrated that loss of Sema7a reduced Kdm4a expression, induced DNA replication stress, and activated the cGAS-STING signaling pathway, thereby increasing IFN-β and CXCL10 secretion. These changes enhanced CD8⁺ T cell chemotaxis and cytotoxic activity, suppressing tumor growth and metastasis in vivo. Conversely, Kdm4a overexpression reversed the antitumor effects of Sema7a deficiency. Our findings establish the Sema7a - Kdm4a axis as a crucial mechanism shaping the immunosuppressive microenvironment in breast cancer and highlight its potential as a therapeutic target to enhance antitumor immunity.
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