IL-9R/Arg1 pathway promotes polyamine metabolism in human airway macrophages

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.

We defined the IL-9/Arg1/polyamine pathway in human macrophages from model systems and asthmatic patient samples.

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.

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 to 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.

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.