IL-13RA2 downregulation in fibroblasts promotes keloid fibrosis via JAK/STAT6 activation

Abstract

Keloid is considered as a fibro-proliferative disease characterized by chronic inflammation that is induced following skin injury. Deciphering the underlying mechanism of keloid formation is essential for improving treatment outcomes. Here, we found that more macrophages were activated towards M2 subtype in keloid dermis when compared to normal dermis. Western Blot revealed that the level of phosphorylated STAT6, a known inducer of M2 polarization, was higher in keloid fibroblasts as opposed to fibroblasts from normal dermis. Moreover, keloid fibrosis was shown to be positively correlated with the level of phosphorylated STAT6. Further, we identified downregulation of IL13RA2, a 'decoy' receptor of IL13, in keloid fibroblasts compared to fibroblasts from normal dermis. Ectopic expression of IL13RA2 in keloid fibroblasts resulted in inhibition of STAT6 phosphorylation, cell proliferation, migration, invasion, extracellular matrix secretion and myofibroblast marker expression, as well as an increase in apoptosis. Consistently, knockdown of IL13RA2 in normal fibroblasts induced a 'keloidal' status. Furthermore, both in vitro application and intra-tumoral injection of pSTAT6 inhibitor AS1517499 in a PDX keloid-implantation mouse model, resulted in proliferation inhibition, tissue necrosis, apoptosis and myofibroblast marker reduction. Collectively, this study elucidates the key role of IL13RA2 in keloid pathology and inspire further translational research of keloid treatment concerning JAK/STAT6 inhibition.

Screening and anti‐glioma activity of Chiloscyllium plagiosum anti‐human IL‐13Rα2 single‐domain antibody

“…With its identification as one of the downstream targets of EGFR and mutant EGFRvIII [36,37], IL-13Rα2 was considered to more easily promote the proliferation, migration and invasion of tumour cells rather than EGFR activation through the Src/PI3K/ Akt/mTOR signalling pathway, whereas EGFR activation mainly promotes cancer cell proliferation [38,39]. JAK-STAT6 signalling pathway was also negative regulated by upstream IL-13Rα2 [25], interestingly, the STAT6 in A172 cells has been found significantly activated due to the inhibition of IL-13Rα2 by targeted siRNA or VNAR (Figure S6), which may contribute to the subsequent inhibitory effect (or apoptosis) of glioma cells. This finding makes IL-13Rα2 a useful target for novel therapies that could be designed to selectively inhibit malignant progression of glioma [40].…”

“…With further studies on IL‐13Rα2, it has been found that IL‐13Rα2 is closely connected with glioma, especially malignant glioma. Rahaman et al [24] demonstrated that the intracellular domain of IL‐13Rα2 can bind type 2 IL‐4Rα and the inhibition was mediated through the interaction between the short intracellular domain of the IL‐13Rα2 protein and the cytoplasmic domain of the IL‐4Rα chain that harbours the STAT6 docking sites, thereby inhibiting the subsequent activation of the Janus tyrosine kinase‐signal transducer and activator of transcription (JAK‐STAT) pathway [25]. This may contribute the development of gliomas.…”

Machine learning and single‐cell transcriptome profiling reveal regulation of fibroblast activation through THBS2/TGFβ1/P‐Smad2/3 signalling pathway in hypertrophic scar

“…Furthermore, we observed positive correlations between CTHRC1 and THBS2 gene expression levels with the presence of IL‐13, TGFB1 and TGFB3. Remarkably, IL‐13 emerged as a pivotal driver of progressive fibrosis and has been found to be elevated in patients with keloid scars 45–48 . Existing reports indicate that IL‐13 induces the production of anti‐apoptotic proteins and directly enhances myofibroblast function, further implicating its role in fibrotic processes 48 .…”

“…Remarkably, IL‐13 emerged as a pivotal driver of progressive fibrosis and has been found to be elevated in patients with keloid scars. 45 , 46 , 47 , 48 Existing reports indicate that IL‐13 induces the production of anti‐apoptotic proteins and directly enhances myofibroblast function, further implicating its role in fibrotic processes. 48 Additionally, the TGF‐β superfamily, well‐established as an important mediator of tissue repair.…”

“… 45 , 46 , 47 , 48 Existing reports indicate that IL‐13 induces the production of anti‐apoptotic proteins and directly enhances myofibroblast function, further implicating its role in fibrotic processes. 48 Additionally, the TGF‐β superfamily, well‐established as an important mediator of tissue repair. 47 The sustained activation of the TGF‐β signalling pathway leads to prolonged and excessive activation of fibroblasts and myofibroblasts, which is necessary for the excessive collagen formation observed in abnormal scars.…”