Vascular smooth muscle cell apoptosis induces interleukin-1-directed inflammation: effects of hyperlipidemia-mediated inhibition of phagocytosis.
BACKGROUND
Atherosclerosis is characterized by lipid accumulation in the vessel wall, inflammation, and both macrophage and vascular smooth muscle cell (VSMC) apoptosis. However, whereas VSMC apoptosis in mice with established atherosclerotic plaques or hyperlipidemia increases serum levels of the proatherogenic cytokines monocyte chemotactic protein (MCP)-1, tumor necrosis factor alpha, and interleukin (IL)-6, the link between hyperlipidemia, apoptosis and inflammation, and the mechanisms by which apoptotic cells promote inflammation in atherosclerosis are unknown.


OBJECTIVE
To determine whether hyperlipidemia affects apoptotic cell clearance, and identify the molecular pathways downstream of VSMC apoptosis that may promote inflammation.


RESULTS
We find that human VSMCs are potent and efficient phagocytes of apoptotic human VSMCs, but phagocytosis is significantly reduced by oxidized low-density lipoprotein in vitro or hyperlipidemia in vivo. Necrotic human aortic VSMCs release IL-1alpha, which induces IL-6 and MCP-1 production from viable human VSMCs in vitro. In contrast, secondary necrotic VSMCs release both IL-1alpha and caspase-activated IL-1beta, augmenting IL-6 and MCP-1 production. Conditionally inducing VSMC apoptosis in situ in hyperlipidemic SM22alpha-hDTR/ApoE(-/-) mice to levels seen in human plaques increases serum MCP-1, tumor necrosis factor alpha, and IL-6, which is prevented by blocking IL-1.


CONCLUSIONS
We conclude that VSMC necrosis releases IL-1alpha, whereas secondary necrosis of apoptotic VSMCs releases both IL-1alpha and beta. IL-1 from necrotic VSMCs induces the surrounding viable VSMCs to produce proinflammatory cytokines. Thus, failed clearance of apoptotic VSMCs caused by hyperlipidemia in vivo may promote the increased serum cytokines and chronic inflammation associated with atherosclerosis.
Clarke
Murray C H
MC
Division of Cardiovascular Medicine, University of Cambridge, Box 110, ACCI, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK. mchc2@cam.ac.uk
Talib
Sara
S
Figg
Nichola L
NL
Bennett
Martin R
MR
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000097:blood / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D006949:Hyperlipidemias / Q000503:physiopathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D053582:Interleukin-1alpha / Q000378:metabolism*; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000469:parasitology; D010587:Phagocytosis / Q000502:physiology
D001057:Apolipoproteins E; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D053582:Interleukin-1alpha; D015850:Interleukin-6