Role of toll-like receptor 4 in intimal foam cell accumulation in apolipoprotein E-deficient mice.
OBJECTIVE
Atherosclerosis encompasses a conspicuously maladaptive inflammatory response that might involve innate immunity. Here, we compared the role of Toll-like receptor 4 (TLR4) with that of TLR2 in intimal foam cell accumulation and inflammation in apolipoprotein E (ApoE) knockout (KO) mice in vivo and determined potential mechanisms of upstream activation and downstream action.


RESULTS
We measured lipid accumulation and gene expression in the lesion-prone lesser curvature of the aortic arch. TLR4 deficiency reduced intimal lipid by ≈75% in ApoE KO mice, despite unaltered total serum cholesterol and triglyceride levels, whereas TLR2 deficiency reduced it by ≈45%. TLR4 deficiency prevented the increased interleukin-1α (IL-1α) and monocyte chemoattractant protein-1 mRNA levels seen within lesional tissue, and it also lowered serum IL-1α levels. Smooth muscle cells (SMC) were present within the intima of the lesser curvature of the aortic arch at this early lesion stage, and they enveloped and permeated nascent lesions, which consisted of focal clusters of foam cells. Cholesterol enrichment of SMC in vitro stimulated acyl-coenzyme A:cholesterol acyltransferase-1 mRNA expression, cytoplasmic cholesterol ester accumulation, and monocyte chemoattractant protein-1 mRNA and protein expression in a TLR4-dependent manner.


CONCLUSIONS
TLR4 contributes to early-stage intimal foam cell accumulation at lesion-prone aortic sites in ApoE KO mice, as does TLR2 to a lesser extent. Intimal SMC surround and penetrate early lesions, where TLR4 signaling within them may influence lesion progression.
Tufts Medical Center, Boston, MA 02111, USA.
Mie
M
Higashimori
Jeffrey B
JB
Tatro
Kathryn J
KJ
Moore
Michael E
ME
Mendelsohn
Jonas B
JB
Galper
Debbie
D
Beasley
D000101:Acetyl-CoA C-Acetyltransferase / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018932:Chemokine CCL2 / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000378:metabolism; D053582:Interleukin-1alpha / Q000097:blood / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D001057:Apolipoproteins E; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D053582:Interleukin-1alpha; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014280:Triglycerides; D019010:Vascular Cell Adhesion Molecule-1; D002784:Cholesterol; C506641:Acat1 protein, mouse; D000101:Acetyl-CoA C-Acetyltransferase