MicroRNAs Are Involved in the Regulation of Immune System during Tumor and Autoinflammation Development

MicroRNAs play important roles in the immune system and their dysregulation leads to diseases. Here we studied two miRNAs, miR-155 and mir-223, in different disease models to demonstrate their function in immune system. As the most heavily studied member of miRNAs, miR-155 is regarded as a regulator of immune cell development and function that is generally thought to be immune-stimulatory. However, we report here that genetic ablation of miR-155 renders mice resistant to chemical carcinogenesis and attenuates the growth of several transplanted tumors, suggesting that miR-155 functions in immunosuppression and tumor promotion. Host miR-155 deficiency promoted overall antitumor immunity despite the finding of defective responses of miR-155-deficient dendritic cells and antitumor T cells. Further analysis of immune cell compartments revealed that miR-155 regulated the accumulation of functional myeloid-derived suppressive cells (MDSC) in the tumor microenvironment. Specifically, miR-155 mediated MDSC suppressor activity through at least two mechanisms, including SOCS1 repression and increased ability to maintain the generation of CD4+Foxp3 + regulatory T cells (Treg). Importantly, we demonstrated that miR-155 expression was required for MDSC to facilitate tumor growth. Thus, our results revealed a contextual function for miR-155 in antitumor immunity, with a role in MDSC support that appears to dominate in tumor-bearing hosts. Overall, the balance of these cellular effects appears to be a root determinant of whether miR-155 promotes or inhibits tumor growth. Apart from the important role they play in the cancers, miRNAs also play a crucial role in the induction and sustained local inflammation observed in neuroinflammatory disorders, such as multiple sclerosis (MS). miR-223, highly expressed in myeloid cell population, is one of the most upregulated miRNAs in MS patient samples. In this study, we investigate the role of miR-223 in experimental autoimmune encephalomyelitis (EAE). We demonstrate that miR-223 KO mice present a milder disease than WT mice. Reduced disease severity was also observed in the adoptive transfer EAE. While M1-like macrophages were upregulated in KO mice, mDCs showed a reduced inflammatory profile characterized by increased PD-L1 expression and decreased expression of IL-1beta, IL-6 and IL-23. Significantly, APCs from miR-223 KO mice have a comparable ability to drive Th1 cells, but possess a reduced capacity to drive Th17 cells. These data reveal an important role for miR-223 in the regulation of mDCs driving pathologic Th17 responses during autoimmune inflammation. Our research suggests a novel clinical intervention to treat MS in the future. Overall, our studies provide more solid evidence that miRNAs play important roles in regulating immune system during the progression of tumor and autoimmune diseases. Furthermore, our results pave the way to find novel therapeutic methods to treat diseases.