Journal Article

Cell-Specific Contribution of IL-4 Receptor α Signaling Shapes the Overall Manifestation of Allergic Airway Disease

Lamichhane, Richa, Patial, Sonika, Vo, Thao, Singamsetty, Dhruthi, Brombacher, Frank, Saini, Yogesh, Choudhary, Ishita

2024

Overview

Abstract IL-4 and IL-13 play a critical role in allergic asthma pathogenesis via their common receptor IL-4Rα. However, the cell-specific role of IL-4Rα in mixed allergen (MA)-induced allergic asthma has remained unclear. Therefore, we aimed to identify the cell-specific contribution of IL-4Rα signaling in the manifestation of various pathological outcomes in mice with allergic airway disease. We compared MA-induced pathological outcomes between hematopoietic progenitor cell (HPC)- or non–HPC-specific IL-4Rα–deficient chimera, myeloid cell–specific IL-4Rα–deficient (LysMcre+/+IL-4Rαfl/fl), and airway epithelial cell–specific IL-4Rα–deficient (CCSP-Cre+/IL-4Rαfl/fl) mice. Chimeric mice with systemic IL-4Rα sufficiency displayed hallmark features of allergic asthma, including eosinophilic and lymphocytic infiltration, type 2 (T-helper type 2) cytokine/chemokine production, IgE production, and lung pathology. These features were markedly reduced in chimeric mice with systemic IL-4Rα deficiency. Non–HPC-specific IL-4Rα–deficient mice displayed typical inflammatory features of allergic asthma but with markedly reduced mucous cell metaplasia (MCM). Deletion of IL-4Rα signaling on airway epithelial cells, a subpopulation within the non-HPC lineage, resulted in almost complete absence of MCM. In contrast, all features of allergic asthma except for MCM and mucin production were mitigated in HPC-specific IL-4Rα–deficient chimeric mice. Deleting IL-4Rα signaling in myeloid cells, a subpopulation within the HPC lineage, significantly alleviated MA-induced allergic airway inflammatory responses, but, similar to the HPC-specific IL-4Rα–deficient chimeric mice, these mice showed significant MCM and mucin production. Our findings demonstrate that the differential allergen responsiveness seen in mice with HPC-specific and non–HPC-specific IL-4Rα deficiency is predominantly driven by the absence of IL-4Rα in myeloid cells and airway epithelial cells, respectively. Our findings also highlight distinct and mutually exclusive roles of IL-4Rα signaling in mediating pathological outcomes within the myeloid and airway epithelial cell compartments.

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Airway management / Allergens - immunology / Allergic diseases / Allergies / Animals / Asthma / Asthma - immunology / Asthma - metabolism / Asthma - pathology / Cells / Chemokines / Epithelial cells / Epithelial Cells - immunology / Epithelial Cells - metabolism / Epithelial Cells - pathology / Hematopoietic stem cells / Hemopoiesis / Immunoglobulin E / Interleukin-4 Receptor alpha Subunit - genetics / Interleukin-4 Receptor alpha Subunit - immunology / Interleukin-4 Receptor alpha Subunit - metabolism / Leukocytes (eosinophilic) / Lung - immunology / Lung - metabolism / Lung - pathology / Lymphocytes T / Metaplasia / Mice / Mice, Inbred C57BL / Mice, Knockout / Original Research / Pathogenesis / Progenitor cells / Receptors, Cell Surface / Respiratory tract diseases / Signal Transduction