MIF Regulates M1 Macrophage Polarization via CD74/CXCR2/JNK Pathway and Mediates Aortic Dissection in Mice

Abstract

Background: Macrophage polarization and VSMC phenotypic switch are important features and critical targets in the progression of Aortic dissection (AD). High expression of MIF in aortic and blood specimens has been observed in patients with AD, but its precise function and mechanism in AD are unknown. We aimed to clarify whether MIF mediates the development of aortic dissection via modulation of M1 macrophage polarization. Methods: Based on the BAPN/Ang II-induced acute aortic dissection model and by intraperitoneal injection of the MIF antagonist ISO-1 to inhibit MIF activity in mice. We assayed macrophage infiltration, polarization, and VSMC phenotypic switching in the aorta of mice in each group. Further, we evaluated the polarizing effects of MIF on RAW264.7 cells directly or indirectly in vitro experiments and explored the specific cellular signaling pathways that mediate its function. At last, we evaluated the role and possible mechanisms of RAW264.7 cells with different degrees of polarization in inducing phenotypic switching of MOVAS cells based on a model of indirect co-culture. Results: Pharmacological inhibition of MIF decreased the incidence of aortic dissection and attenuated aortic vascular remodeling in mice by reducing M1 macrophage infiltration in aorta. In addition, we demonstrated that MIF could activate the intracellular JNK/c-Jun signaling pathway by targeting the CD74/CXCR2 receptor, promote M1 polarization and upregulate the expression of the M1 macrophage markers, iNOS, IL-18, and CD86 in RAW264.7 cells. Further experiments confirmed that upon co-culture with MIF-induced M1 macrophages, the NF-?B pathway was activated in MOVAS cells, inducing the onset of phenotypic switch and apoptosis. Conclusions: The results indicated that MIF mediated macrophage polarization and regulated the progression of aortic dissection, which provided new scientific evidence for the pathogenesis of aortic dissection, and also suggested that MIF may be a potential preventive and therapeutic target for aortic dissection and aortic-related diseases.