CCL2 promotes macrophages-associated chemoresistance via MCPIP1 dual catalytic activities in multiple myeloma

We previously showed that the chemokine CCL2 can recruit macrophages (M phi s) to the bone marrow (BM) in multiple myeloma (MM) and that myeloma-associated M phi s are important in drug resistance. Here, we explore the role of increased CCL2 expression in the BM microenvironment of MM and elucidate the underlying mechanism. Our results show that CCL2 expression is associated with the treatment status of MM patients. M phi s interact with MM cells and further upregulate their expression of CCL2. These increased level of CCL2 polarizes M phi s toward the M2-like phenotype and promotes M phi s to protect MM cells from drug-induced apoptosis. Mechanistically, CCL2 upregulated the expression of the immunosuppressive molecular MCP-1-induced protein (MCPIP1) in M phi s. MCPIP1 mediates M phi s' polarization and protection via dual catalytic activities. Additionally, we found that CCL2 induces MCPIP1 expression via the JAK2-STAT3 signaling pathway. Taken together, our results indicate that increased CCL2 expression in MM patients' BM polarizes M phi s toward the M2-like phenotype and promotes the protective effect of M phi s through MCPIP1, providing novel insight into the mechanism of M phi s-mediated drug resistance in MM.