The migration of leukocytes into inflamed peripheral tissues and lymphoid organs involves a cascade of molecular events finely regulated by chemokines and cell adhesion molecules. Fractalkine (FKN), also known as CX3CL1, is a structurally unique chemokine that can act either as a soluble chemotactic factor or as a membrane-anchored adhesion molecule for circulating leukocytes. It is expressed on endothelial cells, smooth muscle cells, and neurons that are activated by pro-inflammatory cytokines. The FKN receptor (FR), also known as CX3CR1, is expressed on monocytes and mature macrophages, natural killer cells, cytotoxic effector T cells, and mucosal dendritic cells, all of which play important roles in the inflammatory and immune responses.
Accumulating evidence in both clinical studies and animal disease models has shown that FKN signaling is also involved in the pathogenesis of various chronic inflammatory diseases, such as atherosclerosis (Lesnik et al. 2003
), age-related macular degeneration (AMD; Combadiere et al. 2007
), and rheumatoid arthritis (Nanki et al. 2004
). Abrogation of FKN signaling by FR deletion in mice results in reduced accumulation of tissue-specific macrophages, such as foam cells at atherogenic lesions and microglial cells at sites of retinal degeneration. In addition, polymorphisms in human FR, which reduce its binding activity to FKN, have been reported to increase the risk of AIDS and to reduce the risk of coronary artery disease (Faure et al. 2000
, Moatti et al. 2001
). Therefore, the FKN signaling represents a new target for the treatment of an array of inflammatory and immune disorders.
Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear hormone receptor superfamily of ligand-responsive transcription factors (Evans et al. 2004
). It forms a functional heterodimer with the retinoid receptor (RXR)α. Certain lipophilic compounds have been identified as PPARγ ligands that can bind to the receptor complex and stimulate its transcriptional activity. Naturally occurring PPARγ ligands include native and oxidized polyunsaturated fatty acids and arachidonic acid derivatives such as prostaglandins and eicosanoids. Synthetic PPARγ ligands include thiazolidinediones (TZDs) such as rosiglitazone (BRL; Willson & Wahli 1997
). PPARγ regulates a diverse array of physiological processes including adipogenesis, lipid metabolism, and insulin sensitivity, as well as diseases such as obesity, diabetes, and atherosclerosis. The importance of this receptor is accentuated by the widespread use of TZDs as drugs for insulin resistance and type II diabetes.
Numerous studies using mouse genetic models or synthetic PPARγ agonists have suggested that PPARγ also regulates both native and acquired immune responses (Bensinger & Tontonoz 2008
). For example, we have recently reported an unexpected yet important role of PPARγ in suppressing the production of inflammatory milk lipids in the lactating mammary glands, using a mouse model in which PPARγ is specifically deleted in the hematopoietic and endothelial cells. The ingestion of this ‘toxic’ milk by nursing neonates results in growth retardation and inflammatory alopecia (Wan et al. 2007
). Furthermore, conditional deletion of PPARγ in macrophages and intestinal epithelial cells demonstrated that it is important in the regulation of inflammatory bowel disease (Adachi et al. 2006
, Shah et al. 2007
). Surprisingly, macrophage-specific deletion of PPARγ was shown to regulate diet-induced obesity and insulin sensitivity, which are the key components of type II diabetes and metabolic syndrome (Odegaard et al. 2007
To further understand how PPARγ regulates the immune system, we have found that PPARγ activation by rosiglitazone suppresses the FKN signaling via multiple mechanisms. In macrophages, rosiglitazone suppresses both the expression and the membrane translocation of FR. In endothelial cells, rosiglitazone prevents the nuclear export of FKN. Taken together, this evidence provides a previously unrecognized mechanism that may contribute to the anti-inflammatory effect of PPARγ.