Oxidised IL-33 drives COPD epithelial pathogenesis via ST2-independent RAGE/EGFR signalling complex

Area of Science:

• Pulmonary Medicine
• Cell Biology
• Immunology

Background:

• Chronic obstructive pulmonary disease (COPD) involves airway epithelial damage, repair, and remodeling.
• Interleukin-33 (IL-33) signaling via its receptor ST2 mediates inflammation in airway diseases.
• Oxidized IL-33 (IL-33ox) was hypothesized to have limited activity due to reduced ST2 binding.

Purpose of the Study:

• To investigate the functional activities of IL-33ox independent of ST2 in airway epithelium.
• To elucidate the role of IL-33ox in COPD pathogenesis.

Main Methods:

• Utilized in vitro epithelial damage assays and 3D air-liquid interface (ALI) cell culture models of healthy and COPD epithelia.
• Employed bulk and single-cell RNA sequencing to analyze transcriptomic changes in response to IL-33ox and IL-33 neutralization.
• Assessed the interaction of IL-33ox with epithelial receptors.

Main Results:

• IL-33ox forms a complex with the receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR) on airway epithelium.
• This ST2-independent pathway activation impairs epithelial wound closure and induces airway remodeling.
• IL-33ox increases mucus-producing cells and reduces epithelial defense, mimicking COPD traits; pathway neutralization reversed these effects in COPD models.

Conclusions:

• IL-33, RAGE, and EGFR form an ST2-independent pathway in airway epithelium.
• This pathway governs abnormal epithelial remodeling and muco-obstructive features characteristic of COPD.
• Targeting this novel IL-33ox pathway offers a potential therapeutic strategy for COPD.