Regulation Of Macrophage Proliferation And Application Of Macrophage-derived Exosomes In Cancer Chemotherapy

Macrophages derived from monocytes and are found throughout the body.Macrophages are the main immune cells in the innate immune system and play critical roles in the occurrence and development of a variety of diseases based on their self-balancing and repair functions.It has been demonstrated that macrophages are important immune cells involved in tumor development.Meanwhile,macrophages also play an important role in tumor therapy.Revealing the regulatory mechanism underlying the process of macrophage proliferation,migration and apoptosis will be helpful for understanding the occurrence and development of tumor,and is also expected to bring new therapeutic methods for the treatment of tumors.Smurfl(Smad ubiquitination regulatory factor 1),a member of the HECT-type E3 ubiquitin ligases Nedd4 family,plays a critical role in a variety of processes,such as bone homeostasis,development and tumorigenesis.IL-1R8(Interleukin-1 receptor 8),belongs to the IL-1R(IL-1 receptor)family,is a critical immune regulatory factor.It has been demonstrated that IL-1R8 is the receptor of IL-37 and is required for the anti-inflammatory activity of IL-37.Meanwhile,IL-1R8 plays a critical role in liver carcinogenesis and metastasis by regulating the anti-tumor and anti-viral activity of NK cells.Evidence suggests that Smurfl and IL-1R8 play an important physiological role in the development of tumors.However,the role of Smurfl and IL-1R8 in macrophage proliferation,migration and apoptosis remains unknown.Moreover,the role of Smurfl and IL-1R8 in the susceptibility of tumor cells response to chemotherapy is still unclear.Exosomes are nanoparticles with a size range of～40 to 160 nm in diameter,which are produced by all eukaryotic cells and some of the prokaryotic cells and released into the extracellular by exocrine method.Exosomes contains abundant contents,including cytosolic and cell-surface proteins,enzymes,DNA,RNA,lipids,etc.Exosomes can transfer the contents between cells and play a critical role in intercellular communication.Exosomes have attracted more and more attention for the characteristics of low immunogenicity,high stability and good biocompatibility.Therefore,macrophage-derived exsomes,due to their unique tumor-homing ability,can be applied as drug delivery paltforms and thus may be a potential strategy for breast caner-targeted therapies.In this paper,a series of studies are carried out on macrophages and tumors.The main contents and conclusions are as follows:1.Smurfl and IL-1R8 regulate macrophage proliferation:Smurf1 promotes macrophage proliferation by inhibiting p3 8 and JNK activation.IL-1R8 inhibits the activity of the JNK and P38 signaling pathways,and suppresses macrophage proliferation through p38 MAPK signaling pathway rather than the JNK signaling pathway.2.Exosomes with higher purity were isolated from the Macrophage by ultra-centrifugation,The surface protein Lamp2b was modified by the targeted peptide AREYGTRFSLIGGYR(AR).The results showed that the engineered exosomes significantly improve the efficacy of targeted treatment of breast cancer cells.3.Smurf1 inhibits the sensitivity of tumor cells to chemotherapy drugs and reduces the therapeutic effect:In CDX and PDX models,low expression of Smurfl can significantly enhance the sensitivity of colorectal cancer cells to chemotherapy drugs.