Mif ‐deficiency favors an atheroprotective autoantibody phenotype in atherosclerosis

Abstract

The inflammatory cytokine macrophage migration-inhibitory factor (MIF) promotes atherosclerosis via lesional monocyte and T-cell recruitment. B cells have emerged as important components in atherogenesis, but the interaction between MIF and B cells in atherogenesis is unknown. Here, we investigated the atherosclerotic phenotype of Mif-gene deletion in Apoe mice. Apoe Mif mice fed a Western diet exhibited strongly reduced atherosclerotic lesions in brachiocephalic artery (BC) and abdominal aorta compared with controls. This phenotype was accompanied by reduced circulating B cells. Flow cytometry revealed a B-cell developmental defect with increased premature and immature B-cell counts in bone marrow (BM) of Apoe Mif mice and diminished B-cell numbers in spleen. This finding was linked with a decreased expression of Baff-R and differentiation-driving transcription factors at the immature B-cell stage, whereas peritoneal B cells exhibited unchanged CD80 and CD86 expression but vastly decreased CD9 and elevated CD23 levels, indicating that the developmental block favors the generation of immature, egressing, and reactive B cells. Mif deficiency did not affect absolute B-cell numbers in the vessel wall but favored a relative increase of B cells in the atheroprone BC region and the appearance of periadventitial B-cell-rich clusters. Of note, Mif mice exhibited a significant increase in oxidized low-density lipoprotein (oxLDL)-specific antibodies after the injection of oxLDL, indicating that Mif deficiency is associated with higher sensitivity of B cells against natural-occurring antigens such as oxLDL. Importantly, Apoe mice adoptively transplanted with ApoeMif BM showed reduced peripheral B cells compared with Apoe BM transplantation but no atheroprotection in the BC; also, whereas there was a selective increase in atheroprotective IgM-anti-oxLDL-antibodies in global Mif deficiency, BM-specific Mif deficiency also led to elevated proatherogenic anti-oxLDL-IgG. Together, these findings reveal a novel link between MIF and B cells in atherogenesis. Protection from atherosclerosis by Mif deficiency is associated with enhanced B-cell hypersensitivity, which in global but not BM-restricted Mif deficiency favors an atheroprotective autoantibody profile in atherosclerotic mice. Targeting MIF may induce protective B-cell responses in atherosclerosis.-Schmitz, C., Noels, H., El Bounkari, O., Straussfeld, E., Megens, R. T. A., Sternkopf, M., Alampour-Rajabi, S., Krammer, C., Tilstam, P. V., Gerdes, N., Bürger, C., Kapurniotu, A., Bucala, R., Jankowski, J., Weber, C., Bernhagen, J. Mif-deficiency favors an atheroprotective autoantibody phenotype in atherosclerosis.

The macrophage migration inhibitory factor pathway in human B cells is tightly controlled and dysregulated in multiple sclerosis

“…Although abundantly expressed by B cells compared to other immune populations, MIF is downregulated in blood B cells from early MS patients. This downregulation links to the survival of autoreactive naive B cells, as seen in atherosclerotic mice and MS , and coincides with decreased CD74 and increased CXCR4 surface expression, as part of a tightly controlled regulation loop in B cells. The reciprocal expression of CD74 and CXCR4 was supported by the increased migration capacity of B cells toward CXCL12 after inhibition of CD74 .…”

“…Besides functioning as an MHC class II chaperone protein, CD74 also has an MHC class II‐independent role in B‐cell maturation . Interestingly, MIF is also a noncognate ligand for chemokine receptor CXCR4 , which probably cooperate with CD74 to regulate B‐cell development and function through MIF .…”

Porphyromonas gingivalis-Induced MIF Regulates Intercellular Adhesion Molecule-1 Expression in EA.hy926 Cells and Monocyte-Endothelial Cell Adhesion Through the Receptors CD74 and CXCR4

“…In contrast, Mif blockade in mice results in a regression of plaque areas [ 29 ]. Furthermore, antibody inhibition and genetic deletion studies have revealed that MIF influences the promotion of atherosclerosis by enhancing macrophage and T cell recruitment [ 21 , 30 ].…”

Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs

“…MIF/CXCR pathways are drivers in several human diseases. The MIF/CXCR4 signaling axis controls monocyte, T-cell, and B-cell infiltration in atherosclerosis and other inflammatory conditions (17,19). It also contributes to cancer metastasis, cardiac fibroblast survival, and eosinophil inflammation (20,21).…”