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Diversification and CXCR4-Dependent Establishment of the Bone Marrow B-1a Cell Pool Governs Atheroprotective IgM Production Linked to Human Coronary Atherosclerosis.

ABSTRACT: RATIONALE:B-1 cell-derived natural IgM antibodies against oxidation-specific epitopes on low-density lipoprotein are anti-inflammatory and atheroprotective. Bone marrow (BM) B-1a cells contribute abundantly to IgM production, yet the unique repertoire of IgM antibodies generated by BM B-1a and the factors maintaining the BM B-1a population remain unexplored. CXCR4 (C-X-C motif chemokine receptor 4) has been implicated in human cardiovascular disease and B-cell homeostasis, yet the role of B-1 cell CXCR4 in regulating atheroprotective IgM levels and human cardiovascular disease is unknown. OBJECTIVE:To characterize the BM B-1a IgM repertoire and to determine whether CXCR4 regulates B-1 production of atheroprotective IgM in mice and humans. METHODS AND RESULTS:Single-cell sequencing demonstrated that BM B-1a cells from aged ApoE-/- mice with established atherosclerosis express a unique repertoire of IgM antibodies containing increased nontemplate-encoded nucleotide additions and a greater frequency of unique heavy chain complementarity determining region 3 sequences compared with peritoneal cavity B-1a cells. Some complementarity determining region 3 sequences were common to both compartments suggesting B-1a migration between compartments. Indeed, mature peritoneal cavity B-1a cells migrated to BM in a CXCR4-dependent manner. Furthermore, BM IgM production and plasma IgM levels were reduced in ApoE-/- mice with B-cell-specific knockout of CXCR4, and overexpression of CXCR4 on B-1a cells increased BM localization and plasma IgM against oxidation specific epitopes, including IgM specific for malondialdehyde-modified LDL (low-density lipoprotein). Finally, in a 50-subject human cohort, we find that CXCR4 expression on circulating human B-1 cells positively associates with plasma levels of IgM antibodies specific for malondialdehyde-modified LDL and inversely associates with human coronary artery plaque burden and necrosis. CONCLUSIONS:These data provide the first report of a unique BM B-1a cell IgM repertoire and identifies CXCR4 expression as a critical factor selectively governing BM B-1a localization and production of IgM against oxidation specific epitopes. That CXCR4 expression on human B-1 cells was greater in humans with low coronary artery plaque burden suggests a potential targeted approach for immune modulation to limit atherosclerosis.

SUBMITTER: Upadhye A

PROVIDER: S-EPMC6830526 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Diversification and CXCR4-Dependent Establishment of the Bone Marrow B-1a Cell Pool Governs Atheroprotective IgM Production Linked to Human Coronary Atherosclerosis.

Upadhye Aditi A Srikakulapu Prasad P Gonen Ayelet A Hendrikx Sabrina S Perry Heather M HM Nguyen Anh A McSkimming Chantel C Marshall Melissa A MA Garmey James C JC Taylor Angela M AM Bender Timothy P TP Tsimikas Sotirios S Holodick Nichol E NE Rothstein Thomas L TL Witztum Joseph L JL McNamara Coleen A CA

Circulation research 20190924 10

<h4>Rationale</h4>B-1 cell-derived natural IgM antibodies against oxidation-specific epitopes on low-density lipoprotein are anti-inflammatory and atheroprotective. Bone marrow (BM) B-1a cells contribute abundantly to IgM production, yet the unique repertoire of IgM antibodies generated by BM B-1a and the factors maintaining the BM B-1a population remain unexplored. CXCR4 (C-X-C motif chemokine receptor 4) has been implicated in human cardiovascular disease and B-cell homeostasis, yet the role o ...[more]

PMID: 31549940

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Project description: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., Bürger, C., Kapurniotu, A., Bucala, R., Jankowski, J., Weber, C., Bernhagen, J. Mif-deficiency favors an atheroprotective autoantibody phenotype in atherosclerosis.

Dataset Information

Diversification and CXCR4-Dependent Establishment of the Bone Marrow B-1a Cell Pool Governs Atheroprotective IgM Production Linked to Human Coronary Atherosclerosis.

Publications

Diversification and CXCR4-Dependent Establishment of the Bone Marrow B-1a Cell Pool Governs Atheroprotective IgM Production Linked to Human Coronary Atherosclerosis.

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