CCL2 Promotes Macrophages-associated Chemoresistance Via MCPIP1 Dual Catalytic Activities In Multiple Myeloma

Background:Multiple myeloma(MM)is an incurable hematologic malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow(BM).Despite the introduction of novel chemotherapy agents,chemoresistance remains the major problem in clinical management of MM.Regardless,the mechanism of MM chemoresistance has not yet been fully elucidated.Some studies have shown that MM cells possess clonal heterogeneity,and such mutations may result in resistance to chemotherapy.In addition,other studies have reported that the BM plays an essential role in MM chemoresistance,and that the interaction of MM cells with different cell components of the tumor microenvironment is important for tumor growth and chemoresistance.Macrophages(Mφs)are prominsent components in the BM microenvironment of MM.We previously found that Mφs protect MM cells from drug induced apoptosis and the chemokine CCL2 can recruit Mφs to the bone BM in MM.Methods:Clinical significance of CCL2 were investigated by Immunohistochemistry and ELISA.Flow cytometry,quantitative real-time PCR and Western blotting were conducted to evaluated the apoptosis of cells and Mφs’ polarization.RNA sequencing was performed to determinse the key molecular induced by CCL2 in Mφs.Genetically modified cells(e.g.,exhibiting siRNA knockdown or ectopic expression)were employed to evaluate the functional significance of MCPIP1.Proteome Profiler Human phosphor-kinase antibody array was used to determinse the changes of protein phosphorylation in Mφs caused by CCL2.MM xenograft models were used to evaluated the role of CCL2 and MCPIP1 in vivo.Result: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.Mφs interact with MM cells and further upregulate their expression of CCL2.These increased level of CCL2 polarizes Mφs toward the M2-like phenotype and promotes Mφs to protect MM cells from druginduced apoptosis.Mechanistically,CCL2 upregulated the expression of the immunosuppressive molecular MCP-1-induced protein(MCPIP1)in Mφs.MCPIP1 mediates Mφs’ polarization and protection via dual catalytic activities.Additionally,we found that CCL2 induces MCPIP1 expression via the JAK2-STAT3 signaling pathway.Conclusion:our results indicate that increased CCL2 expression in MM patients’ BM polarizes Mφs toward the M2-like phenotype and promotes the protective effect of Mφs through MCPIP1,providing novel insight into the mechanism of Mφs-mediated drug resistance in MM.