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[This article belongs to Volume - 69, Issue - 8]
Published on : 2024-08-10 12:21:36
Article Code: AMJ-10-08-2024-12296
Title : Itaconate Metabolism in Alveolar Macrophages Orchestrates Type 2 Inflammation Resolution in Severe Asthma Through NRF2-Dependent Anti-Inflammatory Programming
Author(s) : Dr. Sophie Dubois, Dr. Mohammed Al-Rashid, Dr. Emily Zhang
Abstract :
Severe eosinophilic asthma is refractory to corticosteroid therapy in 10% of patients, necessitating biologic
interventions. We demonstrate that alveolar macrophages (AMs) from severe asthmatics exhibit defective
immunometabolic programming characterized by diminished itaconate synthesis via mitochondrial aconitate
decarboxylase (ACOD1). Itaconate deficiency resulted in impaired NRF2 antioxidant pathway activation and sustained
IL-4/IL-13 signaling. Intratracheal administration of 4-octyl itaconate (4-OI) in a house dust mite-induced asthma
model restored AM anti-inflammatory phenotype, reduced airway hyperresponsiveness by 60%, and attenuated
mucus hypersecretion. Single-cell metabolomics revealed itaconate-dependent inhibition of succinate
dehydrogenase as the mechanistic link between macrophage metabolism and type 2 inflammation control.
Metabolic reprogramming of AMs represents a novel therapeutic axis for steroid-refractory asthma.