Early Life Represents a Vulnerable Time Window for IL-33-Induced Peripheral Lung Pathology

Area of Science:

• Immunology
• Developmental Biology
• Respiratory Medicine

Background:

• Interleukin-33 (IL-33) is an IL-1 family cytokine found in mucosal tissues, with increased expression during inflammation.
• IL-33 is known to promote type 2 immune responses, but its full functional diversity is not yet understood.

Purpose of the Study:

• To investigate the impact of IL-33 overexpression on lung physiology in a conditional transgenic mouse model.
• To compare the effects of IL-33 overexpression in adult versus neonatal lungs.

Main Methods:

• Development of a conditional IL-33 transgenic mouse model for inducible overexpression in lung epithelial cells.
• Assessment of lung pathology, immune responses, gene expression, and mortality in adult and neonatal mice with IL-33 overexpression.
• Evaluation of the role of the IL-33 receptor ST2 by using deficient mice.

Main Results:

• Adult mice with IL-33 overexpression showed no lung pathology at steady-state but exhibited enhanced type 2 immune responses upon allergen exposure.
• Neonatal mice with IL-33 overexpression (up to postnatal day 14) experienced increased mortality, lung alveolar enlargement, and altered tissue morphogenesis gene expression.
• Pathologic changes in neonatal mice were linked to processed IL-33 and were abrogated in ST2-deficient mice.

Conclusions:

• Adult lungs demonstrate relative resistance to IL-33 overexpression unless challenged by environmental factors.
• Developing lungs are highly susceptible to IL-33 overexpression, leading to detrimental outcomes and bronchopulmonary dysplasia-like changes.
• These findings highlight the critical role of IL-33 in lung development and its differential impact based on age and environmental stimuli.