Dual oxidase: a novel therapeutic target in allergic disease

Abstract

NADPH oxidases (NOXs) represent a family of enzymes that mediate regulated cellular production of reactive oxygen species (ROS) and play various functional roles in physiology. Among the NOX family, the dual oxidases DUOX1 and DUOX2 are prominently expressed in epithelial cell types at mucosal surfaces and have therefore been considered to have important roles in innate host defence pathways. Recent studies have revealed important insights into the host defence mechanisms of DUOX enzymes, which control innate immune response pathways in response to either microbial or allergic triggers. In this review, we discuss the current level of understanding with respect to the biological role(s) of DUOX enzymes and the unique role of DUOX1 in mediating innate immune responses to epithelial injury and allergens and in the development of allergic disease. These novel findings highlight DUOX1 as an attractive therapeutic target, and opportunities for the development of selective inhibitor strategies will be discussed. AbbreviationsCPZ, chlorpromazine; DPI, diphenylene iodonium; DUOX, dual oxidase; DUOXA, dual oxidase maturation factor; EGFR, EGF receptor; ER, endoplasmic reticulum; HDM, house dust mite; ILC2, type 2 innate lymphoid cell; LPO, lactoperoxidase; MPO, myeloperoxidase; NOX, NADPH oxidase; NOXA, NOX activator; PDB, protein database; PHD, peroxidase homology domain; ROS, reactive oxygen species; TK, tyrosine kinase; TLR, toll-like receptor; TPO, thyroperoxidase; TRX, thioredoxin IntroductionThe concept of oxidative stress has been widely embraced as a major factor in disease pathology and has fuelled a billion dollar industry based on antioxidant dietary supplements. However, clinical studies using antioxidant supplementation strategies have generally been unsuccessful in attenuating disease risk or progression, and antioxidant supplementation was in some cases found to even worsen pathological outcomes (Ghezzi et al., 2017). This lack of success likely relates to the flawed concept of oxidative stress as a pharmacological target. First, oxidative stress can be brought about by a range of ROS (the commonly used acronym to define this group of reactive metabolites), which can originate from external sources (e.g. environmental pollution and metabolism of xenobiotics) or be generated endogenously by various enzymatic systems, in some cases in a regulated and deliberate fashion to serve important biological functions [e.g. by activation of NADPH oxidases (NOXs)]. Therefore, generic non-selective approaches that indiscriminately suppress ROS may not have the desired outcome. A second flaw with such generic antioxidant approaches is the fact that ROS represent a diverse group of reactive metabolites that each have unique (bio)chemical properties, and it is often unclear to what extent antioxidant supplements counter the action of individual ROS species. To clarify this, it is helpful to distinguish primary from secondary ROS, with primary ROS representing the initial products of (enzymatic) O 2 reduction [i.e. superoxi...

NOX5: Molecular biology and pathophysiology

“…Duox1 and Duox2 are Ca 2+ ‐activated Noxs that localize primarily in epithelial cells at mucosal surfaces and are highly expressed in the thyroid gland. Duox1/2 play an important role in thyroid hormone biosynthesis (Carvalho & Dupuy, ) and have recently been shown to be involved in mediating innate immune responses (van der Vliet, Danyal, & Heppner, ).…”

The genetic structure and adaptation of Andean highlanders and Amazonian dwellers is influenced by the interplay between geography and culture

“…It was reported as a natural selection target in the Andes by 43,44 . DUOX2 encodes a trans-membrane component of an NADPH oxidase, which produces hydrogen peroxide (H 2 O 2 ), and is essential for the synthesis of the thyroid hormone and for the production of microbicidal hypothiocyanite anion (OSCN-) during mucosal innate immunity response against bacterial and viral infections in the airways and intestines 45,46 . Mutations in DUOX2 produce inherited hypothyroidism 47 Before the introduction of the public health program of supplementing manufactured salt with iodine, one of the environmental stresses of the Andes for human populations was iodine deficiency, which impairs thyroid hormone synthesis, increasing the risk of developing hypothyroidism, goiter, obstetric complications and cognitive impairment 49,50 .…”

Mini review: immunologic functions of dual oxidases in mucosal systems of vertebrates

“…In some cases, viral infection can also induce the expression of DUOX1 (Grandvaux et al, 2015). However, DUOX1 is a commonly critical protein in the pathogenesis of allergic airways according to its association with type 2 immune responses and the its ability to interact with type 2 cytokines (Comhair and Erzurum, 2010;Sugiura and Ichinose, 2008;Suzuki et al, 2016;Van der Vliet et al, 2018). IL-4 and IL-13, can recruit neutrophils in airways to promote allergic asthma (Chang et al, 2013).…”