Allergic airway disease is unaffected by the absence of IL-4Rα-dependent alternatively activated macrophages

Background: Markers of alternatively activated macrophages (AAMs) are upregulated in the lungs of asthmatic patients and in mice with allergic airway disease. AAMs are thought to contribute to the pathogenesis of allergic airway disease by virtue of their decreased NO production and increased production of proline and polyamines, which are important in the synthesis of connective tissues such as collagen. Objective: We aimed to define the role of AAMs in the pathogenesis of allergic airway disease. Methods: The IL-4 receptor alpha (IL-4Rα) gene is genetically abrogated in macrophages in LysM creIL-4Rα-/lox mice, which therefore have impaired IL-4/IL-13 activation of AAMs through IL-4R types 1 and 2. Responses of LysMcreIL-4Rα-/lox mice and IL-4Rα -/lox littermate controls were examined in ovalbumin- and house dust mite-induced allergic airway disease. Results: IL-4Rα expression was shown to be efficiently depleted from alveolar macrophages, interstitial macrophages, and CD11b+MHCII+ inflammatory macrophages. Although the expression of markers of AAMs such as Ym-1, arginase and found in inflammatory zone 1 was decreased in macrophages of LysMcreIL-4Rα -/lox mice in chronic ovalbumin-induced allergic airway disease, airway hyperreactivity, TH2 responses, mucus hypersecretion, eosinophil infiltration, and collagen deposition were not significantly reduced. LysMcreIL-4Rα-/lox mice and littermate controls also developed similar responses in acute ovalbumin- and house dust mite-induced allergic airway disease. Conclusion: Our results suggest that the presence of AAMs in allergic airway disease may be only an association, as a result of the increased TH2 responses present during disease, and that IL-4Rα-dependent AAMs do not play an important role in the pathology of disease. © 2012 American Academy of Allergy, Asthma & Immunology.