Impact of macrophage inflammatory protein-1α deficiency on atherosclerotic lesion formation, hepatic steatosis, and adipose tissue expansion.

Macrophage inflammatory protein-1α (CCL3) plays a well-known role in infectious and viral diseases; however, its contribution to atherosclerotic lesion formation and lipid metabolism has not been determined. Low density lipoprotein receptor deficient (LDLR(-/-)) mice were transplanted with bone marrow from CCL3(-/-) or C57BL/6 wild type donors. After 6 and 12 weeks on western diet (WD), recipients of CCL3(-/-) marrow demonstrated lower plasma cholesterol and triglyceride concentrations compared to recipients of C57BL/6 marrow. Atherosclerotic lesion area was significantly lower in female CCL3(-/-) recipients after 6 weeks and in male CCL3(-/-) recipients after 12 weeks of WD feeding (P<0.05). Surprisingly, male CCL3(-/-) recipients had a 50% decrease in adipose tissue mass after WD-feeding, and plasma insulin, and leptin levels were also significantly lower. These results were specific to CCL3, as LDLR(-/-) recipients of monocyte chemoattractant protein(-/-) (CCL2) marrow were not protected from the metabolic consequences of high fat feeding. Despite these improvements in LDLR(-/-) recipients of CCL3(-/-) marrow in the bone marrow transplantation (BMT) model, double knockout mice, globally deficient in both proteins, did not have decreased body weight, plasma lipids, or atherosclerosis compared with LDLR(-/-) controls. Finally, there were no differences in myeloid progenitors or leukocyte populations, indicating that changes in body weight and plasma lipids in CCL3(-/-) recipients was not due to differences in hematopoiesis. Taken together, these data implicate a role for CCL3 in lipid metabolism in hyperlipidemic mice following hematopoietic reconstitution.

Absence of macrophage inflammatory protein-1{alpha} does not impact macrophage accumulation in adipose tissue of diet-induced obese mice.

Macrophages and T-lymphocytes are known to accumulate in the white adipose tissue (WAT) of obese mice and humans, but the factors that cause this infiltration are not yet determined. Chemokines, which attract leukocytes to inflammatory sites, are candidates for this process. Macrophage inflammatory protein-1alpha (MIP-1alpha) expression is significantly elevated in WAT of obese mice and humans and positively correlates with fasting plasma insulin, but its potential role in leukocyte recruitment to WAT is unknown. MIP-1alpha-deficient, heterozygous, and wild-type mice were fed a Western diet (WD) for 16 wk. Plasma lipids, adipose tissue mass, energy expenditure, food intake, liver triglyceride content, and inflammatory cytokine expression were not different among genotypes. Gene expression of macrophage markers F4/80 and CD68, as well as T-lymphocyte marker CD3epsilon was increased in perigonadal WAT of obese WD-fed mice but was not influenced by MIP-1alpha expression level. Immunohistochemical analysis of WAT also showed no effect of MIP-1alpha on macrophage content. Two related chemokines, MIP-1beta and RANTES, had reduced expression in obese male MIP-1alpha-deficient mice compared with wild-type controls (P < or = 0.05). In mice fed the WD for 6 wk, WAT macrophage content was unchanged; however, CD8+ T-lymphocytes accumulated to a lesser extent in the MIP-1alpha-null mice. Therefore, expression of MIP-1alpha, as well as that of MIP-1beta and RANTES, increases as a consequence of weight gain, but these chemokines may not be required for the recruitment of monocytes to WAT during diet-induced obesity in mice and may impact T-lymphocyte recruitment only at early time points after WD feeding.

The role of chemokines in recruitment of immune cells to the artery wall and adipose tissue.

The role of the immune system is to recognize pathogens, tumor cells or dead cells and to react with a very specific and localized response. By taking advantage of a highly sophisticated system of chemokines and chemokine receptors, leukocytes such as neutrophils, macrophages, and T-lymphocytes are targeted to the precise location of inflammation. While this is a beneficial process for acute infection and inflammation, recruitment of immune cells to sites of chronic inflammation can be detrimental. It is becoming clear that these inflammatory cells play a significant role in the initiation and progression of metabolic disorders such as atherosclerosis and insulin resistance by infiltrating the artery wall and adipose tissue (AT), respectively. Data from human studies indicate that elevated plasma levels of chemokines are correlated with these metabolic diseases. Recruitment of macrophages to the artery wall is well known to be one of the first steps in early atherosclerotic lesion formation. Likewise, recruitment of macrophages to AT is thought to contribute to insulin resistance associated with obesity. Based on this knowledge, much recent work in these areas has focused on the role of chemokines in attracting immune cells (monocytes/macrophages in particular) to these 2 sites. Thus, understanding the potential for chemokines to contribute to metabolic disease can help direct studies of chemokines as therapeutic targets. In this article, we will review current literature regarding the role of chemokines in atherosclerosis and obesity-related insulin resistance. We will focus on novel work showing that chemokine secretion from endothelial cells, platelets, and adipocytes can contribute to immune cell recruitment, with a diagram showing the time course of chemokine expression and leukocyte recruitment to AT. We will also highlight a few of the less-commonly known chemokine-chemokine receptor pairs. Finally, we will discuss the potential for chemokines as therapeutic targets for treatment of atherosclerosis and insulin resistance.

Macrophage infiltration into adipose tissue: initiation, propagation and remodeling.

It has long been known that adipose tissue in obesity is in a heightened state of inflammation. Recently, our understanding of this has been transformed by the knowledge that immune cells such as macrophages and T cells can infiltrate adipose tissue and are responsible for the majority of inflammatory cytokine production. These seminal findings have opened up a new area in biology that is garnering the interest of scientists involved in research relating to cell motility, inflammation, obesity, physiology, diabetes and cardiovascular disease. Some important general questions relevant to this field are: how are macrophages recruited to adipose tissue in obesity? What are the physiological consequences of macrophage-adipocyte interactions? Do these inflammatory macrophages contribute to pathophysiological conditions associated with obesity, such as insulin resistance, dyslipidemia, diabetes and cardiovascular disease? This review focuses on the first of these important questions.

The role of macrophage leptin receptor in aortic root lesion formation.

Plasma leptin is often elevated in obese individuals, and previous studies have suggested leptin as a factor that links obesity and atherosclerosis. Because macrophages play a key role in atherogenesis and are responsive to leptin, we hypothesized that leptin increases aortic root lesion formation, in part, through macrophage leptin receptor (LepR). Three different bone marrow transplantation studies were conducted in which bone marrow, with or without LepR, was transplanted into lethally irradiated 1) LDL receptor-deficient (LDLR(-/-)) mice with moderate hyperleptinemia due to Western diet (WD) feeding, 2) LDLR(-/-) mice with WD feeding plus pharmacologically induced hyperleptinemia (daily injection of 125 microg leptin), or 3) obese, hyperleptinemic, LepR-deficient LDLR(-/-) (LepR(db/db);LDLR(-/-)) mice. Minor differences in plasma parameters such as cholesterol, triglycerides, and insulin were observed in some groups; however, a consistent trend for the role of LepR on these parameters was not detected. In each of the studies, macrophage LepR expression did not have an effect on aortic root atherosclerotic lesion formation. These results suggest that nonhematopoietic cells may have a more significant role than macrophages in leptin-mediated effects on aortic root lesion formation.

Effects of vitamin E on oxidative stress and atherosclerosis in an obese hyperlipidemic mouse model.

Vitamin E is a natural antioxidant that has been used in animal and human studies to determine its potential in reducing cardiovascular risk; however, a detailed study in an established obese model of atherosclerosis has yet to be performed. In our current study, we show that obesity and hyperlipidemia cause a synergistic, age-related increase in urinary isoprostane levels in mice deficient in both leptin and low-density lipoprotein receptor (ob/ob;LDLR-/-). Based upon this observation, we hypothesized that vitamin E supplementation would induce potent antiatherogenic effects in this model. Lean and obese LDLR-/- mice were provided vitamin E (2000 IU/kg) in a Western-type high-fat diet for 12 weeks. Plasma lipid parameters, such as total cholesterol (TC), triglyceride (TG) and free fatty acid, were significantly higher in obese mice compared to lean mice at baseline (P<.001). Western-type diet (WD) feeding caused an increase in TC levels in all groups (P<.001); however, TG (P<.001) and free fatty acid (P<.01) were elevated only in lean mice following WD feeding. Vitamin E supplementation neither influenced any of these parameters nor reduced urinary isoprostanes in lean or obese mice. Vitamin E supplementation in ob/ob;LDLR-/- mice resulted in a trend toward a reduction in atherosclerotic lesion area (P=.10), although no differences in lesion area were noted in lean LDLR-/- animals. These data provide evidence that vitamin E supplementation is not sufficient to reduce extreme elevations in systemic oxidative stress due to hyperlipidemia and obesity and, thus, may not be cardioprotective in this setting.