B-cell-specific depletion of tumour necrosis factor alpha inhibits atherosclerosis development and plaque vulnerability to rupture by reducing cell death and inflammation

Christopher Tay, Yu Han Liu, Hamid Hosseini, Peter Kanellakis, Anh Cao, Karlheinz Peter, Peter Tipping, Alex Bobik, Ban Hock Toh, Tin Kyaw

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28 Citations (Scopus)

Abstract

Aims 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. Methods and results 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. Conclusion 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.

Original languageEnglish
Pages (from-to)385-397
Number of pages13
JournalCardiovascular Research
Volume111
Issue number4
DOIs
Publication statusPublished - 1 Sep 2016

Keywords

  • Apoptosis
  • Atherosclerosis
  • B2 cells
  • Inflammation
  • TNF-α

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