IL-9R/Arg1 pathway promotes polyamine metabolism in human airway macrophages
Year: 2026
Type: article
Abstract: Background Lung macrophages are central regulators of inflammatory responses in the airways and lung parenchyma. Macrophages function as conduits for cytokine function in the inflammatory milieu. We previously demonstrated that IL-9-responsive macrophages are essential for allergic lung inflammation in an arginase 1 (Arg1) pathway. Objective Define the IL-9/Arg1/polyamine pathway in human macrophages from model systems and asthmatic patient samples. Methods Using humanized NSG-Quad mice treated with intranasal IL-9 and patient bronchoalveolar lavage (BAL) samples, we evaluated macrophage phenotypes via flow cytometry, bulk RNA sequencing, and metabolic assays. Results Two distinct human lung macrophage populations were defined by the expression of CD43. IL-9 promoted the expansion of IL-9R+/Arg1+ CD43- macrophages in humanized mice. In parallel, greater proportions of IL-9R+/Arg1+ CD43- macrophages were observed in asthmatic patient BAL samples compared with healthy control patients. Higher concentrations of polyamines, downstream metabolites of Arg1 function, were detected in BAL of IL-9-treated humanized mice. There were increased concentrations of polyamines in asthmatic patient BAL, compared to control samples, and concentrations were positively correlated to BAL IL-9 concentration and increases of IL-9R+ and Arg1+ CD43- macrophages. Conclusions IL-9-responsive CD206+ CD43- macrophages alter the metabolites present in the lung milieu. These data provide evidence for an IL-9R/Arg1/polyamine lung macrophage axis that is active in asthma patients.
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,900
Funders: American Lung Association, Riley Children's Foundation, National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Th9 cells in immediate hypersensitivity, G2229616563, FOXP3 ΔE2 isoform in asthma severity and persistence, Molecular regulation of protective CD8 immunity against influenza infection, IL-9-dependent interstitial macrophage function in the allergic lung, G4940684865, G6237288963, Basic Sciences Studies on Gene Therapy of Blood Diseases, G7321284031, BD FACSAria System, G8323017467, G9000025480, Scientific innovation for personalized severe asthma management, G9000304140, Uncover mechanisms underlying the development of chronic lung sequelae post COVID-19, Immunology and Infectious Diseases Training Program, CD38, T cells and post viral lung sequelae during aging, Determinants of Convalescent and Vaccine-induced Mucosal Specific Immunity to SARS-CoV-2 and Variants of Concern in Children with Asthma, Host cellular network governing the development of post SARS-CoV-2 tissue sequelae, Hematopoietic stem and progenitor cell regulation for enhanced clinical efficacy, Elucidating the roles of alveolar macrophage inflammation and self renewal during influenza infection, Indiana University Melvin and Bren Simon Comprehensive Cancer Center Support Grant
OpenAlex ID: W7207825099