MEF2C Regulates M1 Polarization And Th1 Cells Response

Macrophage is an important innate immune cell and it can produce various inflammatory cytokines and chemokines when stimulated by pathogens.In addition,macrophages also can directly engulf and kill invading pathogens with strong phagocytosis and antigen presenting ability to regulate the innate immunity and adaptive immunity homeostasis in the process of resisting pathogens.Macrophages are a heterogeneous population of immune cells that are essential for the initiation and resolution of pathogen induced inflammation.They prove considerable plasticity that allows them to respond efficiently to environmental signals and change their phenotype and physiology in response to cytokines and microbial signals.Current studies confirm that two macrophage subsets,termed Ml and M2,the former is considered proinflammatory and the latter anti-inflammatory,are involved in immune balance regulation in response to different microenvironments.Myocyte enhancer factor-2 C(MEF2C)is a specific transcription factor,and it belongs the family of the MEF2.Studies have shown that MEF2C plays important roles in many processes,such as nervous system development,cardiac morphogenesis,muscle cell differentiation,blood vessel formation.In this study,we used siRNA to knockdown the expression of MEF2C gene in macrophages,we found that many M1 markers expression were down-regulated,such as IL-12/IL-23/iNOS etc,however,many M2 markers expression were up-regulated,such as IL-10/Arg-1 ete after LPS stimulation.Overexpression experiments got the similar results,suggesting that MEF2C took part in regulating the polarization of macrophages.Then,we induced Ml and M2 in a classical way,and the results showed that MEF2C was high-expressed in MI cells and low-expressed in M2 cells,which further suggested that MEF2C played an important role in the macrophages polarization·Next,we got the mice with MEF2C condition knockout in macrophages.We found that M1 marker CD11c expression was down-regulated and M2 marker CD206 was up-regulated in MEF2C-deficient macrophages by flow cytometry analysis.We further established the inflammation model induced by LPS and listeria infection in vivo.The results showed that gene expression related with macrophages polarization consistent with in vitro.Besides,we found that MEF2C-deficiency mice were more susceptible to listeria infection,and the listeria loads in the spleen and liver compared with the control group was significantly increased,and the HE staining showed that liver injury was more serious in MEF2C-deficient mice.Furthermore,MEF2C-deficient macrophages became significantly weaken in killing listeria.Our results also revealed that MEF2C deficiency in macrophages could damage Thl response.Mechanically,we confirmed that Mef2c could be directly regulation of IL-12/IL-10 transcriptional by double luciferase reporter gene assay and ChIP experiment.Collectively,we elucidated a crucial role for MEF2C in regulating macrophages polarization and Thl cell response by promoting IL-12/IL-10 production,and then regulating the innate immunity and adaptive immune response.