# Protective Role for Itaconate During Inhaled Allergen Challenge

## TL;DR

This study explores how itaconate, a metabolite, affects airway inflammation in asthma when allergens are inhaled.

## Contribution

The study identifies itaconate's protective role in allergic airway inflammation and suggests its potential as a therapeutic strategy.

## Key findings

- Itaconate levels decrease in sputum following allergen inhalation in mild asthmatics.
- Inhaled itaconate reduced airway inflammation in house dust mite-exposed mice.
- Genetic deletion of Acod1 in mice did not alter airway inflammation from chronic allergen exposure.

## Abstract

Asthma is a chronic, heterogeneous disease characterised by airway remodelling, inflammation, and mucus production. Airway macrophages' functions are underpinned by changes in cellular metabolism. The TCA cycle‐derived metabolite itaconic acid (whose synthesis is mediated by aconitate decarboxylase) is a master regulator of macrophage function; however, its role during inhaled allergen challenge is not clear. The objective of this study was to define the role of itaconate during inhaled allergen challenge.

Sputum metabolite levels were measured in participants with mild allergic asthma undergoing allergen inhalation challenge, and in a second cohort, baseline levels in mild, moderate, and severe asthmatics. Airway inflammation, lung function, and bronchoalveolar lavage metabolite levels were assessed in wild‐type and aconitate decarboxylase‐deficient mice, or in mice treated with inhaled itaconate.

Allergen inhalation in mild asthmatics led to a significant reduction in sputum itaconate. We found no difference in baseline sputum itaconate levels when comparing healthy controls to mild, moderate, or severe asthmatics. Continuous exposure to aeroallergen in wild type and aconitate decarboxylase‐deficient mice showed no change in disease phenotype after 48 h, 1, 3, or 5 weeks of allergen exposure. Treatment of house dust mite‐exposed mice with inhaled itaconate reduced airway inflammation.

Levels of itaconate are altered after allergen challenge in mild asthmatics and in murine models of disease. Itaconate deficiency did not alter house dust mite‐induced pathology at any of the timepoints tested; however, inhaled itaconate ameliorated inflammatory responses to inhaled allergen.

Itaconate levels decrease in sputum following allergen inhalation in mild asthmatics, suggesting a dynamic metabolic response to airway challenge. Genetic deletion of Acod1 in mice did not alter airway inflammation or remodelling in response to chronic HDM exposure. Inhaled itaconate treatment reduced airway inflammation in HDM‐exposed mice, highlighting its potential as a therapeutic strategy for allergic airway disease. Abbreviations: Acod1, aconitate decarboxylase; AMs, airway macrophages; BAL, bronchoalveolar lavage; Ccl5, C‐C motif chemokine ligand 5; Ctrl, control; Cxcl1, C‐X‐C motif chemokine ligand 1; DCs, dendritic cells; HDM, house dust mite; Tgfb1, transforming growth factor beta 1; WT, wild type.