Stat6, Signal Transducer and Activator of Transcription 6, is a transcription factor central to pro-allergic immune responses, primarily stimulated by interleukin(IL)-4 and IL-13, and acts as a T helper type 2 (Th2)-inducing factor [2]. It is involved in multiple biological processes and is implicated in the pathophysiology of various allergic conditions, tumor microenvironment regulation, and certain forms of lymphomas [2]. Genetic models, such as KO mouse models, are valuable for studying its functions.

In stroke mouse models, STAT6 deficiency led to reduced clearance of dead/dying neurons, increased inflammatory gene signature in microglia/macrophages, enlarged infarct volume, increased brain tissue loss, and exacerbated long-term functional deficits, suggesting that STAT6/Arg1 signaling axis is crucial for microglia/macrophage efferocytosis and inflammation resolution after stroke [1]. In keloid formation, downregulation of IL-13RA2 in fibroblasts promoted keloid fibrosis via JAK/STAT6 activation, and inhibition of p-STAT6 could reduce keloid fibroblast proliferation [3]. In oxalate crystal deposition-induced renal fibrosis, STAT6 promoted macrophage-to-myofibroblast transition by inhibiting fatty acid oxidation, and pharmacological inhibition of STAT6 prevented renal injury and fibrosis [4].

In conclusion, Stat6 is essential in regulating immune-related and fibrotic processes. The study of Stat6 using KO mouse models has revealed its key roles in diseases like stroke, keloid formation, and renal fibrosis, providing potential therapeutic targets for these conditions.

References:

1. Cai, Wei, Dai, Xuejiao, Chen, Jie, Hu, Xiaoming, Chen, Jun. 2019. STAT6/Arg1 promotes microglia/macrophage efferocytosis and inflammation resolution in stroke mice. In JCI insight, 4, . doi:10.1172/jci.insight.131355. https://pubmed.ncbi.nlm.nih.gov/31619589/

2. Karpathiou, Georgia, Papoudou-Bai, Alexandra, Ferrand, Elise, Dumollard, Jean Marc, Peoc'h, Michel. 2021. STAT6: A review of a signaling pathway implicated in various diseases with a special emphasis in its usefulness in pathology. In Pathology, research and practice, 223, 153477. doi:10.1016/j.prp.2021.153477. https://pubmed.ncbi.nlm.nih.gov/33991851/

3. Chao, Hua, Zheng, Lisheng, Hsu, Pojui, Liu, Haibo, Tang, Qing. 2023. IL-13RA2 downregulation in fibroblasts promotes keloid fibrosis via JAK/STAT6 activation. In JCI insight, 8, . doi:10.1172/jci.insight.157091. https://pubmed.ncbi.nlm.nih.gov/36757802/

4. Yuan, Tianhui, Xia, Yuqi, Pan, Shengyu, Zhou, Xiangjun, Cheng, Fan. 2023. STAT6 promoting oxalate crystal deposition-induced renal fibrosis by mediating macrophage-to-myofibroblast transition via inhibiting fatty acid oxidation. In Inflammation research : official journal of the European Histamine Research Society ... [et al.], 72, 2111-2126. doi:10.1007/s00011-023-01803-2. https://pubmed.ncbi.nlm.nih.gov/37924395/