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Schmitz, Corinna; Noels, Heidi; El Bounkari, Omar; Straussfeld, Eva; Megens, Remco T. A.; Sternkopf, Marieke; Alampour-Rajabi, Setareh; Krammer, Christine; Tilstam, Pathricia V.; Gerdes, Norbert; Bürger, Christina; Kapurniotu, Aphrodite; Bucala, Richard; Jankowski, Joachim; Weber, Christian; Bernhagen, Jürgen (2018): Mif-deficiency favors an atheroprotective autoantibody phenotype in atherosclerosis. In: FASEB Journal, Vol. 32, No. 8: pp. 4428-4443
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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 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., Burger, C., Kapurniotu, A., Bucala, R., Jankowski, J., Weber, C., Bernhagen, J. Mif-deficiency favors an atheroprotective autoantibody phenotype in atherosclerosis.