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

Abstract

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.

Figure 1. Regulation of specific chemokines and leukocytes in AT of high fat diet fed mice

The diagram indicates only the initial upregulation of each chemokine during high fat diet feeding and is based on the following references: (Jiao et al., 2009; Nishimura et al., 2009). Numbers on blue arrows represent the number of weeks on high fat diet. The initial reported increase or decrease in each cell type is shown; the horizontal arrows indicate that high fat diet fed mice continue to have more macrophages and CD8+ T-lymphocytes and fewer CD4+ T-lymphocytes and Treg lymphocytes throughout high fat diet feeding. Additional sources used: (Weisberg et al., 2003; Xu, H. et al., 2003; Caspar-Bauguil et al., 2005; Coenen et al., 2007; Strissel et al., 2007; Takahashi et al., 2007; Rausch et al., 2008; Duffaut et al., 2009a; Feuerer et al., 2009; Winer et al., 2009) Note to editor: Please combine these two slides into on figure with this panel below the first slide.

Figure 1. Regulation of specific chemokines and leukocytes in AT of high fat diet fed mice

The diagram indicates only the initial upregulation of each chemokine during high fat diet feeding and is based on the following references: (Jiao et al., 2009; Nishimura et al., 2009). Numbers on blue arrows represent the number of weeks on high fat diet. The initial reported increase or decrease in each cell type is shown; the horizontal arrows indicate that high fat diet fed mice continue to have more macrophages and CD8+ T-lymphocytes and fewer CD4+ T-lymphocytes and Treg lymphocytes throughout high fat diet feeding. Additional sources used: (Weisberg et al., 2003; Xu, H. et al., 2003; Caspar-Bauguil et al., 2005; Coenen et al., 2007; Strissel et al., 2007; Takahashi et al., 2007; Rausch et al., 2008; Duffaut et al., 2009a; Feuerer et al., 2009; Winer et al., 2009) Note to editor: Please combine these two slides into on figure with this panel below the first slide.