Fibroblast-derived CCL2 driven by MIF promotes joint capsule fibrosis via macrophage polarization regulation

Post-traumatic joint contracture (PTJC) is driven by persistent joint capsule inflammation and subsequent fibrosis. CC motif chemokine ligand 2 (CCL2) is recognized as a key regulator of sustained inflammation. However, the relevant regulatory mechanism involved in CCL2 production in PTJC has not been fully elucidated. In this study, we investigated whether MIF can facilitate CCL2 production from fibroblasts and regulate joint capsule fibrosis following PTJC. Our data demonstrated that PTJC-induced elevation of CCL2 levels was synchronous with MIF. Administration of MIF inhibitor 4-IPP at the lesion sites significantly reduced the expression of CCL2. An in vitro study revealed that MIF potently facilitated the production of CCL2 in joint capsule fibroblasts through interaction with CD74 receptor and subsequent activation of JNK/CREB signaling. Interestingly, fibroblast-derived CCL2 promoted macrophage excessive polarization toward M2 phenotype through the CC motif chemokine receptor 2 (CCR2), thereby amplifying chronic inflammation and fibrosis. The inhibition of MIF activity prevented the pro-fibrotic process by decreasing CCL2. Our results provide insights into the new functions of MIF-mediated CCL2 production in fibroblasts, which exacerbates the pathological microenvironment by tuning joint capsule inflammation and fibrosis during PTJC. The present study may provide a new therapeutic strategy for other inflammation- and fibrosis-associated diseases.