Macrophage-intrinsic DUOX1 contributes to type 2 inflammation and mucus metaplasia during allergic airway disease

• DOI: 10.1038/s41385-022-00530-x
• Publication Date: 2022-06-02T11:06:43Z
• Authors: Carolyn R. Morris; Aida Habibovic; Christopher M. Du...; Caspar Schiffers; Miao-Chong Lin; Jennifer L. Ather; Yvonne M.W. Janss...; Matthew E. Poynter; Olaf Utermohlen; Martin Krönke; Albert van der Vliet
• Keywords: Inflammation; 0301 basic medicine; Metaplasia; Macrophages; Pyroglyphidae; 610; ddc:no; Allergens; Dual Oxidases; Article; Mucus; 03 medical and health sciences; Hypersensitivity; Airway Remodeling; Animals; Antigens, Dermatophagoides; Lung

The NADPH oxidase DUOX1 contributes to epithelial production of alarmins, including interleukin (IL)-33, in response to injurious triggers such as airborne protease allergens, and mediates development of mucus metaplasia and airway remodeling in chronic allergic airways diseases. DUOX1 is also expressed in non-epithelial lung cell types, including macrophages that play an important role in airway remodeling during chronic lung disease. We therefore conditionally deleted DUOX1 in either lung epithelial or monocyte/macrophage lineages to address its cell-specific actions in innate airway responses to acute airway challenge with house dust mite (HDM) allergen, and in chronic HDM-driven allergic airway inflammation. As expected, acute responses to airway challenge with HDM, as well as type 2 inflammation and related features of airway remodeling during chronic HDM-induced allergic inflammation, were largely driven by DUOX1 with the respiratory epithelium. However, in the context of chronic HDM-driven inflammation, DUOX1 deletion in macrophages also significantly impaired type 2 cytokine production and indices of mucus metaplasia. Further studies revealed a contribution of macrophage-intrinsic DUOX1 in macrophage recruitment upon chronic HDM challenge, as well as features of macrophage activation that impact on type 2 inflammation and remodeling.