title: B-cell-specific depletion of tumour necrosis factor alpha inhibits atherosclerosis development and plaque vulnerability to rupture by reducing cell death and inflammation.
abstract: B2 lymphocytes promote atherosclerosis development but their mechanisms of action are unknown. Here, we investigated the role of tumour necrosis factor alpha (TNF-α) produced by B2 cells in atherogenesis.
  
  
  
  We found that 50% of TNF-α-producing spleen lymphocytes were B2 cells and ∼20% of spleen and aortic B cells produced TNF-α in hyperlipidemic ApoE(-/-) mice. We generated mixed bone marrow (80% μMT/20% TNF-α(-/-)) chimeric LDLR(-/-) mice where only B cells did not express TNF-α. Atherosclerosis was reduced in chimeric LDLR(-/-) mice with TNF-α-deficient B cells. TNF-α expression in atherosclerotic lesions and in macrophages were also reduced accompanied by fewer apoptotic cells, reduced necrotic cores, and reduced lesion Fas, interleukin-1β and MCP-1 in mice with TNF-α-deficient B cells compared to mice with TNF-α-sufficient B cells. To confirm that the reduced atherosclerosis is attributable to B2 cells, we transferred wild-type and TNF-α-deficient B2 cells into ApoE(-/-) mice deficient in B cells or in lymphocytes. After 8 weeks of high fat diet, we found that atherosclerosis was increased by wild-type but not TNF-α-deficient B2 cells. Lesions of mice with wild-type B2 cells but not TNF-α-deficient B2 cells also had increased apoptotic cells and necrotic cores. Transferred B2 cells were found in lesions of recipient mice, suggesting that TNF-α-producing B2 cells promote atherosclerosis within lesions.
  
  
  
  We conclude that TNF-α produced by B2 cells is a key mechanism by which B2 cells promote atherogenesis through augmenting macrophage TNF-α production to induce cell death and inflammation that promote plaque vulnerability.
authors: Vascular Biology and Atherosclerosis Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, Faculty of Medicine, Nursing and Health Sciences. Monash University, 246 Clayton Road, Clayton, Victoria 3168, Australia.
authors: Christopher
authors: C
authors: Tay
authors: Vascular Biology and Atherosclerosis Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
authors: Yu-Han
authors: YH
authors: Liu
authors: Vascular Biology and Atherosclerosis Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, Faculty of Medicine, Nursing and Health Sciences. Monash University, 246 Clayton Road, Clayton, Victoria 3168, Australia.
authors: Hamid
authors: H
authors: Hosseini
authors: Vascular Biology and Atherosclerosis Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
authors: Peter
authors: P
authors: Kanellakis
authors: Vascular Biology and Atherosclerosis Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, Faculty of Medicine, Nursing and Health Sciences. Monash University, 246 Clayton Road, Clayton, Victoria 3168, Australia.
authors: Anh
authors: A
authors: Cao
authors: Atherothrombosis and Vascular Biology Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
authors: Karlheinz
authors: K
authors: Peter
authors: Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, Faculty of Medicine, Nursing and Health Sciences. Monash University, 246 Clayton Road, Clayton, Victoria 3168, Australia.
authors: Peter
authors: P
authors: Tipping
authors: Vascular Biology and Atherosclerosis Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
authors: Alex
authors: A
authors: Bobik
authors: Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, Faculty of Medicine, Nursing and Health Sciences. Monash University, 246 Clayton Road, Clayton, Victoria 3168, Australia.
authors: Ban-Hock
authors: BH
authors: Toh
authors: Vascular Biology and Atherosclerosis Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, Faculty of Medicine, Nursing and Health Sciences. Monash University, 246 Clayton Road, Clayton, Victoria 3168, Australia tinsoe.kyaw@bakeridi.edu.au.
authors: Tin
authors: T
authors: Kyaw
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism*; D016923:Cell Death; D059305:Diet, High-Fat; D007249:Inflammation / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D014409:Tumor Necrosis Factor-alpha
keywords: Apoptosis; Atherosclerosis; B2 cells; Inflammation; TNF-α