Oxidative stress serves as a key checkpoint for IL‐33 release by airway epithelium

Abstract

Background Interleukin (IL)-33 is implicated in the pathophysiology of asthma and allergic diseases. However, our knowledge is limited regarding how IL-33 release is controlled. The transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a key role in antioxidant response regulation. Objective The goal of this project was to investigate the role of cellular oxidative stress in controlling IL-33 release in airway epithelium. Methods Complementary approaches were used that included human bronchial epithelial cells and mouse models of airway type-2 immunity that were exposed to fungus Alternaria extract. The clinically available Nrf2 activator 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me) was used to evaluate the role of Nrf2-induced antioxidant molecules. Results Human bronchial epithelial cells produced reactive oxygen species (ROS) when they were exposed to Alternaria extract. ROS scavengers, such as glutathione (GSH) and N-acetyl cysteine, prevented extracellular secretion of ATP and increases in intracellular calcium concentrations that precede IL-33 release. Administration of CDDO-Me to mice enhanced expression of a number of antioxidant molecules in the lungs and elevated lung levels of endogenous GSH. Importantly, CDDO-Me treatment reduced allergen-induced ATP secretion and IL-33 release by airway epithelial cells in vitro and protected mice from IL-33 release and asthma-like pathological changes in the lungs. Conclusions The balance between oxidative stress and antioxidant responses plays a key role in controlling IL-33 release in airway epithelium. The therapeutic potential of Nrf2 activators needs to be considered for asthma and allergic airway diseases.

Interleukin‐33 (IL‐33): A nuclear cytokine from the IL‐1 family

“…Therefore, A. alternata ‐induced cell death or damage could be the major mechanism of IL‐33 release in vivo. This would not exclude an important role of extracellular ATP or oxidative stress in the regulation of epithelial cell death and IL‐33 release. Indeed, administration of P2 purinergic receptor antagonists or antioxidant glutathione has been shown to attenuate IL‐33 release in BAL fluids after intranasal exposure to A. alternata .…”

“…Human IL‐33 95‐270 and IL‐33 109‐270 are likely to be major mature forms of IL‐33 in vivo because they can be generated by both activated neutrophils and IgE‐activated mast cells. In mouse, mature forms of IL‐33 of 19‐20 kDa have been detected in BAL fluids after acute lung injury or exposure to fungal aeroallergen Alternaria alternata , and in the lungs in response to chitin or migratory helminths …”

“…Fungal allergen A. alternata has been proposed to induce IL‐33 release in the absence of cell death, via cellular stress, through extracellular secretion of ATP, increases in intracellular calcium concentration, and generation of reactive oxygen species (ROS) . A. alternata is a potent inducer of IL‐33 release in vivo .…”

The R213G polymorphism in SOD3 protects against allergic airway inflammation

“…A potential link between oxidative stress and inflammation is IL-33, which is one of the most potent alarmins that activate type II innate lymphoid cells (ILC2s) (29). Allergen exposure, specifically Alternaria, induces oxidative stress in bronchial epithelial cells that causes extracellular secretion of ATP and increases intracellular calcium concentrations preceding IL-33 release from the airway epithelium (30). IL-33 is stored in the nucleus and is released upon cellular activation (29).…”

Oxidative Stress: Promoter of Allergic Sensitization to Protease Allergens?

“…In mice administration of a Nrf2 activator, a master regulator of antioxidant machinery, protected against IL-33 release and the allergic immune responses. These data underline the role of oxidative stress in the initiation of the allergic cascade [28]. In addition, there could be an amplifying effect via type 2 innate lymphoid cells secreting IL-13.…”