Mif‐deficiency favors an atheroprotective autoantibody phenotype in atherosclerosis

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_l_ mice adoptively transplanted with Apoe−/−Mif−/− 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. FASEB J. 32, 4428‐4443 (2018). www.fasebj.org