Duox2-flox Mouse

DUOX2, short for Dual Oxidase 2, is a key enzyme involved in the production of hydrogen peroxide. It plays a role in innate defense responses, such as in the gut-epithelial cells where the release of hydrogen peroxide by DUOX is a primordial innate defense mechanism [2]. In the thyroid, DUOX2 is crucial for thyroid hormone biosynthesis [1,3,6]. Its function is associated with pathways related to immune-microbiota homeostasis, viral defense in respiratory epithelial cells, and tumorigenesis in the context of colonic inflammation [2,4,5]. Genetic models, especially gene knockout (KO) or conditional knockout (CKO) mouse models, can be valuable for studying its function.

In congenital hypothyroidism (CH), DUOX2 is the most frequently mutated gene in the Chinese population. Biallelic and triple variants of DUOX2 are common in children with thyroid dysgenesis (TD) and gland-in-situ (GIS), types of CH. The residual enzymatic activity of DUOX2 is closely related to the clinical phenotypes of CH patients caused by DUOX2 biallelic mutations, with 22% residual activity potentially being a cutoff for estimating hypothyroidism severity [1,3]. In inflammatory bowel disease (IBD), rare loss-of-function variants of DUOX2 are associated with increased plasma levels of interleukin-17C, a marker for epithelial activation by gram-negative bacteria, suggesting DUOX2 as an IBD risk gene [2]. In virus-infected respiratory epithelial cells, DUOX2 deficiency selectively reduces the induction of certain cytokines and chemokines, affecting neutrophil attraction and activation [4]. In colitis-associated neoplasia, epithelial TLR4 signaling activates DUOX2, leading to increased epithelial hydrogen peroxide production and microbiota-driven tumorigenesis. TLR4-dependent tumorigenesis requires DUOX2 and a microbiota [5].

In conclusion, DUOX2 is essential for thyroid hormone biosynthesis and plays important roles in maintaining microbiota-immune homeostasis, responding to viral infections in the respiratory tract, and in colonic tumorigenesis. Studies using KO or CKO mouse models have revealed its role in these disease-related biological processes, contributing to our understanding of the pathogenesis of congenital hypothyroidism, IBD, and colitis-associated neoplasia.