Interleukin-13 (IL-13)-A Pleiotropic Cytokine Involved in Wound Healing and Fibrosis

Abstract

The liver, as a central metabolic organ, is systemically linked to metabolic-inflammatory diseases. In the pathogenesis of the metabolic syndrome, inflammatory and metabolic interactions between the intestine, liver, and adipose tissue lead to the progression of hepatic steatosis to metabolic-dysfunction-associated steatohepatitis (MASH) and consecutive MASH-induced fibrosis. Clinical and animal studies revealed that IL-13 might be protective in the development of MASH through both the preservation of metabolic functions and Th2-polarized inflammation in the liver and the adipose tissue. In contrast, IL-13-associated loss of mucosal gut barrier function and IL-13-associated enhanced hepatic fibrosis may contribute to the progression of MASH. However, there are only a few publications on the effect of IL-13 on metabolic diseases and possible therapies to influence them. In this review article, different aspects of IL-13-associated effects on the liver and metabolic liver diseases, which are partly contradictory, are summarized and discussed on the basis of the recent literature.

Keywords: IL-13; MASH; MASLD; NAFLD; NASH; fibrosis; liver; metabolism.

Figure 1

Signaling pathways for IL-13 in various scenarios. Illustration of the three cell membrane receptors that bind IL-4, IL-13, or both according to [20]. IL-4-type I receptor consists of the IL-4Rα subunit and γc. This receptor, which is mainly expressed on hematopoietic cells, binds to IL-4. This binding leads to the activation of JAK1, JAK2, and JAK3 and the subsequent phosphorylation of STAT6. The type II receptor consists of IL-4Rα and IL-13Rα1 (it is found, for example, on smooth muscle cells, fibroblasts, and keratinocytes). Ligand binding of the type II receptor complex leads to activation of JAK1, JAK2, and TYK2 and the subsequent phosphorylation of STAT6 and STAT3. Activated STAT dimers migrate into the nucleus and trigger the activation of downstream genes. IL-13 signals only via the type II receptor. IL-13 also binds to an IL-13Rα2 receptor, whose functions are largely unknown. IL-13 signaling through IL-13Rα2 can lead to STAT6-independent phosphorylation of ERK1/2 and formation of the dimeric transcription factor AP-1. The phosphorylated AP-1 subsequently migrates into the nucleus.

Figure 2

The complex interaction and action of IL-13 in different organs and different cells within one organ is depicted in the figure according to [33,34,59]. Blue arrows depict up- and down-regulation. Ko, knockout; IL, interleukin; HSC, hepatic stellate cells.