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

Abstract

We previously showed that the chemokine CCL2 can recruit macrophages (Mφs) to the bone marrow (BM) in multiple myeloma (MM) and that myeloma-associated Mφs 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. 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 drug-induced 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. Taken together, 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.

CCL2 Expression in Tumor Cells and Tumor-Infiltrating Immune Cells Shows Divergent Prognostic Potential for Bladder Cancer Patients Depending on Lymph Node Stage

“…Recently, Xu et al could show that increased levels of CCL2 polarize macrophages in multiple myelomas toward the M2-like phenotype that generally suppresses antitumor immunity [45]. They suggest as a mechanism that CCL2 upregulates the expression of the immunosuppressive molecular MCP-1-induced protein (MCPIP1) in macrophages [45]. However, we did not see differences in the number of M2-like macrophages (CD163 positive) between N0 and N1+2 patients.…”

“…In a mouse tumor model from a breast metastasis cell line (MDA-MB-231), stimulation of CCL2 expression by M2 macrophages was recently shown [42]. Recently, Xu et al could show that increased levels of CCL2 polarize macrophages in multiple myelomas toward the M2-like phenotype that generally suppresses antitumor immunity [45]. They suggest as a mechanism that CCL2 upregulates the expression of the immunosuppressive molecular MCP-1-induced protein (MCPIP1) in macrophages [45].…”

The Role of Tumor Microenvironment in Multiple Myeloma Development and Progression

“…In fact, although M2 macrophages can be detected in BM from MM independently of the stage disease, the grade of infiltration and its correlation with poor prognosis is notable within relapsed MM patients compared to patients with MGUS or SMM [ 138 , 145 ]. In line with these data, some serum receptors such as soluble CD206 and CD163, as well as chemokines like CCL2 and MIF have been proposed as biomarkers for disease progression, prognosis and treatment response [ 38 , 146 , 147 , 148 ].…”

Does C-C Motif Chemokine Ligand 2 (CCL2) Link Obesity to a Pro-Inflammatory State?

“…In turn, CCL2 upregulates the expression of MCP-1-induced protein (MCPIP1) in macrophages which triggers their polarization into the M2 phenotype that protects the myeloma cells from drug-induced apoptosis. Therefore, therapeutic strategies targeting MCPIP1 could be promising to enhance the chemotherapeutic effect [ 166 ].…”