The Role of IL-13 and IL-4 in Adipose Tissue Fibrosis

Abstract

White adipose tissue (WAT) fibrosis, characterized by an excess of extracellular (ECM) matrix components, is strongly associated with WAT inflammation and dysfunction due to obesity. Interleukin (IL)-13 and IL-4 were recently identified as critical mediators in the pathogenesis of fibrotic diseases. However, their role in WAT fibrosis is still ill-defined. We therefore established an ex vivo WAT organotypic culture system and demonstrated an upregulation of fibrosis-related genes and an increase of α-smooth muscle actin (αSMA) and fibronectin abundance upon dose-dependent stimulation with IL-13/IL-4. These fibrotic effects were lost in WAT lacking il4ra, which encodes for the underlying receptor controlling this process. Adipose tissue macrophages were found to play a key role in mediating IL-13/IL-4 effects in WAT fibrosis as their depletion through clodronate dramatically decreased the fibrotic phenotype. IL-4-induced WAT fibrosis was partly confirmed in mice injected intraperitoneally with IL-4. Furthermore, gene correlation analyses of human WAT samples revealed a strong positive correlation of fibrosis markers with IL-13/IL-4 receptors, whereas IL13 and IL4 correlations failed to confirm this association. In conclusion, IL-13 and IL-4 can induce WAT fibrosis ex vivo and partly in vivo, but their role in human WAT remains to be further elucidated.

EP300 as a Molecular Integrator of Fibrotic Transcriptional Programs

“…When activated, immune cells highly express factors that promote fibroblast activation. Even though the specific immune cells and the mediators promoting fibroblast activation vary from one fibrotic disease to another, a common feature is the type 2 immune response, more importantly via the secretion of interleukin 13 and 14 (IL-13 and IL-4) produced by T-helper type 2 (TH2) cells, which in turn leads to M2-polarized macrophages with a subsequent release of profibrotic molecules that promote the activation and accumulation of myofibroblasts [18,19]. Myofibroblasts refer to a cellular phenotype characterized by stellate-shaped cells with high levels of intracellular proteins such as non-muscle myosin, alpha smooth-muscle actin (αSMA), and vimentin and differentiated from diverse sources (pericytes, endothelial cells, fibrocytes, epithelial cells, and resident fibroblasts).…”

Multimodal Strategies to Fight Obesity: Research on Tailored Therapies Based on Natural and Synthetic Compounds for Prevention, Management and Treatment

“…The authors demonstrated that this effect is dependent on WAT-associated macrophages, since their removal by clodronate liposome treatment decreased the fibrotic deposition in WAT in mice intraperitoneally injected with IL-4. A strong positive correlation between fibrosis markers and IL-13/IL-4 receptors was found, but the data seem to indicate that both IL-13 and IL-4 can play a role in ex vivo WAT systems, though only partly in in vivo models [ 18 ].…”