Nuclear Control of the Inflammatory Response in Mammals by Peroxisome Proliferator-Activated Receptors
Figure 2
Representative illustration of PPAR main targets in inflammatory diseases. PPARα mostly displays anti-inflammatory properties in the context of liver inflammation. Its reported liver targets are hepatocytes and Küppfer cells [131]. IL-1β produced by Küppfer cells potently suppresses Pparα expression and activity via NF-B–dependent inhibition of PPARα promoter activity [160]. Besides downregulating gene expression of proinflammatory mediators such as Mcp-1, Tnf-α, Ifn-γ, IL-1β, and PPARα also directly controls expression of IL1-ra in liver [131, 163]. Küppfer cell activation is also dependent on PPARβ/δ, which also targets stellate cells and therefore prevents liver fibrosis [75, 138]. In addition, PPARβ/δ has well-established anti-inflammatory properties in diseases associated with CNS inflammation. In CNS, PPARβ/δ has also proven anti-inflammatory properties in neurons, glial cells, and astrocytes [200–202]. PPARγ anti-inflammatory properties are mainly illustrated in T2D and IBD. PPARγ serves as the molecular target of the insulin-sensitizing TZD drugs and plays a key role in T2D, adipogenesis and obesity. In WAT, mature adipocytes, Treg cells and macrophages have been identified as key cellular targets for PPARγ [66, 75, 116, 117]. Macrophage-specific deletion of PPARγ leads to specific reduction in alternatively activated macrophages (M2 state) in WAT leading to local inflammation [110]. Moreover, Treg-cell-specific deletion of Pparγ was shown to reduce the abundance of Treg cells in WAT resulting in the increase of WAT infiltration by proinflammatory macrophages (M1) and monocytes [116, 117]. In IBD, PPARγ acts in intestinal epithelial cells, macrophages and lymphocytes [190–192]. Note that endotoxemia represses the mRNA expression level of Ppars (see black bar) [150–155]. Furthermore, multiple lines of evidence indicated that PPARγ is very important in endothelial cells, because it inhibits the in situ production of proinflammatory molecules such as vascular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and MCP-1 [215, 223–228]. Similar conclusions were also drawn for the PPARα and PPARβ/δ isotypes [214, 216–220]. Finally, PPARs display protective effets against endotoxemia [166, 167, 169, 236]. NASH: nonalcoholic steatoHepatitis; T2D: type-2 diabetes; CNS: central nervous system; Treg cells: Foxp3+ CD4+ regulatory T cells; DIO: diet-induced-obesity; APR: acute phase response; green lines: action of PPARα; blue lines: action of PPARβ/δ; purple lines: action of PPARγ; ?: Some PPARγ-independent effects of PPARγ activators have been proposed [146, 147]; : pharmacological activation of PPARβ/δ did not protect against dextran sulfate sodium-induced colitis pointing towards a ligand-independent anti-inflammatory effect of PPARβ/δ [180].
