Mast cells promote atherosclerosis by releasing proinflammatory cytokines

Jiusong Sun, et al. Nature Medicine.2007; 13:719-724

Speaker: 陳倩怡                               Time: 14:00~15:00, Nov 28, 2007

Commentator: 蔡曜聲 老師                  Place: Room 601

Abstract:

The inflammatory infiltrate in human atherosclerotic lesions includes mast cells. Compared with Ldlr⁻/⁻mice, Ldlr̄⁻/⁻Kit w-sh/w-sh mice showed reduced atherosclerotic lesion grade in the aortic arch after consuming a Western diet for 26 weeks and also showed reductions in the tunica intima area but not in the tunica media area, at both 12- and 26- week time points, indicating that mast cells may operate more in the intima than in the underlying tunica media. These results indicated that it is mast cell deficiency, rather than altered c-kit signaling , that reduces atherosclerosis in Ldlr⁻/⁻ Kit w-sh/w-sh mice ,thus establishing a direct role for mast cells in atherosclerosis. Besides, mast cell derived proinflammatory cytokines may be critical in promoting atherosclerosis. To test this possibility, the authors reconstituted Ldlr⁻/⁻Kit w-sh/w-sh mice with BMMC from IL-6,IFN-γ,TNF-α-deficient mice .Notably, Tnf ⁻/⁻ mast cell-reconstituted Ldlr⁻/⁻Kit w-sh/w-sh mice had atherosclerotic lesion grades and intimal leision sizes comparable to those in Ldlr⁻/⁻ mice or in Ldlr⁻/⁻Kit w-sh/w-sh mice reconstituted with wild-type mast cells. In contrast ,reconstituted of Ldlr⁻/⁻Kit w-sh/w-sh mice with mast cells lacking IL-6 or IFN-γ did not affect tunica media size ,but the mice had significantly lower lesion grades and intimal sizes than did Ldlr⁻/⁻ mice or than did Ldlr⁻/⁻Kit w-sh/w-sh mice reconstituted with wild-type or Tnf⁻/⁻ mast cells, implying that mast cell derived IL-6 and IFN-γ participate importantly in mouse atherogenesis.In addition, the authors cultured mouse aortic SMC or vascular endothelial cells together with BMMC from wild-type,IL6⁻/⁻,Ifng⁻/⁻ or Tnf⁻/⁻ mice. Coculture with IL-6⁻/⁻ BMMC showed significant cathepsin induction in SMC but not in endothelial cells ,and coculture with Ifng⁻/⁻ BMMC showed minimal effects in either cell type, implying a local effect of mast cell-derived IL-6 and IFN-γ on extracellular matrix degradation.

These studies help resolve about the role of mast cell in atherosclerosis.

References:

1. Ilze Bot, Saskia C.A. de Jager, Alma Zernecke, Ken A. Lindstedt, Theo J.C. van Berkel, Christian Weber, and Erik A.L. Biessen Perivascular Mast Cells Promote Atherogenesis and Induce Plaque Destabilization in Apolipoprotein E–Deficient Mice. Circulation 2007; 115:2516-2525

2. Libby, P. Inflammation in atherosclerosis. Nature 2002; 420: 868-874