The Regulation Of KDM2B In Innate Immune Responses And The Underlying Epigenetic Mechanism

The inflammatory response induced by the innate immune system is an important mean for the body to resist pathogen invasion.The organism relies on innate immunity and inflammatory responses to effectively defence and remove pathogen infection.However,the excessive or persistent inflammatory reaction activation can lead to the injury of important organs and tissues.In the organism,the development process of the innate immune response and inflammatory diseases triggered by pathogens or endogenous ligands involves the expression regulation of a lot of key genes.The epigenetic modification is a key way to regulate gene expression,which can directly affect on gene transcription of some cytokines,or target important signaling molecules to adjust their gene expression,eventually regulates the immune response.Histone modification as an important form of the epigenetic modifications plays an important role in the regulation of gene expression,and is involved in many pathophysiological processes such as inflammation,tumor development and autoimmune diseases.Methylation is a common form of histone modifications.Previous studies find that histone methylation modification mainly functions through regulating histone methylation status of genes to change their expression levels,and then controls the growth and development of immune cells and apoptosis,participating in the body's immune response.Histone methylation modification is a process that is regulated by histone methyltransferases and histone demethylases,which mainly act on the lysine and arginine of histones.In recent years,studies have found that many histone modification enzymes have played an important role in the regulation of innate immune responses.Histone H3K4 methyltransferases MLL and WDR5 can promote the expression of cytokine TNF-?,histone H3K9 methyltransferases Suv39h1 and Setdb1 are associated with the expression of cytokine IL-2,and histone H3K27 demethylases JMJD3 and UTX can promote the expression of inflammatory cytokines.In addition,the same type of modification in different genes may produce the opposite effects.For example,histone methyltransferase Ash1 l inhibits the expression of cytokines through modifying the methylation level of H3K4 on the promoter of target gene which is different with the genes targeted by MLL and WDR5.Therefore,exploring the regulatory mechanism of histone modification is of great significance for the in-depth study of regulation of the innate immune response and inflammatory response.In this study,we focus on the histone demethylase KDM2 B,which is also known as Jhdm1 b or Fbxl10 and a histone H3K4me3 and H3K36me2 demethylase located in the nucleus.Previous studies have showed that KDM2 B can regulate apoptosis,inhibit cell senescence,and regulate the self-renewal of hematopoietic stem cells,the formation of the neural tube and the development of embryo.KDM2 B also participates in the development of tumor.However,the role of KDM2 B in the innate immune response and inflammatory response remains unclear.Our study found that the expression level of KDM2 B was higher in macrophages of mice,and decreased after TLR4 ligand LPS stimulation.KDM2 B silencing inhibited the production of IL-6 but not TNF-? and IFN-? in peritoneal macrophages stimulated with TLR.We successfully generated KDM2 B knockout mice,and found that KDM2 B deficiency significantly suppressed TLR-induced production of IL-6 but not TNF-? and IFN-? in peritoneal macrophages,and did not affect IFN-? production triggered by VSV or HSV virus.The production of IL-6 but not TNF-? in serum and the inflammatory injury of lung was markedly decreased in KDM2 B knockout mice challenged by LPS intraperitoneal injection.In DSS-induced colitis model,KDM2 B knockout mice showed less weight loss and IL-6 production in serum as well as intestinal inflammation injury.KDM2 B deficiency did not affect LPS-induced activation of MAPK,NF-?B and IRF3 signaling pathway.KDM2 B binds the promoter regions of IL-6,but not IFN-? and TNF-? promoter upon LPS stimulation,and also did not affect H3K4me3 and H3K36me2 levels of these three genes' promoter.Through mass spectrometric analysis of the immunoprecipitation complex immunoprecipitated by KDM2 B Ab from lysis of macrophages stimulated with LPS for 1 h,BRG1,the core catalysis subunit of SWI/SNF chromatin remodeling complex functioning in changing the chromatin accessibility of target gene promoter,was found to interact with KDM2 B,which was further comfirmed by immunoprecipitation assay in LPS-stimulated macrophages utilized with KDM2 B Ab.Furthermore,KDM2 B deficiency decreased the chromatin accessibility of Il6 promoter in macrophages upon LPS stimulation.Collectively,our data indicate that KDM2 B selectively promotes TLR-induced IL-6 production and enhances inflammatory responses.The underlying mechanism may be that KDM2 B interacts with BRG1,and then increases the chromatin accessibility of Il6 promoter through BRG1 in macrophages upon TLR activation,which needs to be further investigation.Thus,our study uncovers the novel function of histone demethylase KDM2 B in epigenetic regulation of innate immune responses and inflammation,which may provide a new potential target and direction for clinical intervention of infectious and inflammatory diseases.