Impact of macrophage Toll-like receptor 4 deficiency on macrophage infiltration into adipose tissue and the artery wall in mice

Vanderbilt University Medical Centre, Room 702 Light Hall, Nashville, TN 37232-0615, USA.
Diabetologia (Impact Factor: 6.67). 02/2009; 52(2):318-28. DOI: 10.1007/s00125-008-1221-7
Source: PubMed


Toll-like receptor 4 (TLR4) is a receptor for saturated fatty acids (SFAs), global deficiency of which has been shown to protect against inflammation, insulin resistance and atherosclerotic lesion formation. Because macrophages express Tlr4 and are important in insulin resistance and atherosclerotic lesion formation due to their infiltration of white adipose tissue (WAT) and the artery wall, respectively, we hypothesised that deficiency of macrophage TLR4 could protect against these disorders.
Bone marrow transplantation of agouti, LDL-receptor deficient (A(y)/a; Ldlr (-/-)) mice with marrow from either C57BL/6 or Tlr4 (-/-) mice was performed. Recipient mice with Tlr4 (+/+) marrow (MthetaTLR4(+/+)) or with Tlr4 (-/-) marrow (MthetaTLR4(-/-)) were then placed on one of four diets: (1) low fat; (2) high fat; (3) high fat rich in SFAs (HF(SFA)); and (4) HF(SFA) supplemented with fish oil.
There were no differences in body composition or plasma lipids between MthetaTLR4(+/+) and MthetaTLR4(-/-) mice on any of the diets. However, we observed a decrease in some macrophage and inflammatory markers in WAT of female low fat-fed MthetaTLR4(-/-) mice compared with MthetaTLR4(+/+) mice. MthetaTLR4(-/-) mice fed low-fat diet also displayed decreased atherosclerotic lesion area. There were no differences in macrophage accrual in WAT or atherosclerosis between MthetaTLR4(+/+) and MthetaTLR4(-/-) mice fed any of the high-fat diets. Finally, no difference was seen in insulin sensitivity between MthetaTLR4(+/+) and MthetaTLR4(-/-) mice fed the HF(SFA) diet.
These data suggest that under certain dietary conditions, macrophage expression of Tlr4 can be an important mediator of macrophage accumulation in WAT and the artery wall.

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    • "However, the authors found no role for TLR4-deficient bone marrow-derived cells in the development of atherosclerosis in this model [27]. In contrast, transplantation of bone marrow from Tlr4−/− mice into Ldlr−/− recipients, followed by feeding a high-cholesterol, low-fat diet, resulted in reduced atherosclerosis compared with mice transplanted with wild type bone marrow [71]. Overall, these results imply that endogenous ligands activate TLR4 in vascular cells, leading to proatherogenic effects. "
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