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Published on: April 14, 2010
Allergic airway disease is unaffected by the absence of IL-4Rα-dependent alternatively activated macrophages
Natalie E Nieuwenhuizen1, Frank Kirstein, Jaisubash Jayakumar
1International Center for Genetic Engineering and Biotechnology, Cape Town, South Africa.
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(cre)IL-4Rα(-/lox) mice, which therefore have impaired IL-4/IL-13 activation of AAMs through IL-4R types 1 and 2. Responses of LysM(cre)IL-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 LysM(cre)IL-4Rα(-/lox) mice in chronic ovalbumin-induced allergic airway disease, airway hyperreactivity, T(H)2 responses, mucus hypersecretion, eosinophil infiltration, and collagen deposition were not significantly reduced. LysM(cre)IL-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 T(H)2 responses present during disease, and that IL-4Rα-dependent AAMs do not play an important role in the pathology of disease.
Insights
Alternatively activated macrophages (AAMs) are associated with allergic airway disease but do not drive its pathology. Genetic ablation of IL-4Rα in macrophages did not alter disease severity, suggesting AAMs are not key players.
Area of Science:
- Immunology
- Respiratory Medicine
- Cell Biology
Background:
- Alternatively activated macrophages (AAMs) are implicated in allergic airway diseases like asthma.
- AAMs are hypothesized to worsen disease through reduced nitric oxide and increased collagen synthesis.
Purpose of the Study:
- To investigate the functional role of AAMs in the pathogenesis of allergic airway disease.
- To determine if impairing AAM activation affects disease development and severity.
Main Methods:
- Utilized LysM(cre)IL-4Rα(-/lox) mice with genetically abrogated IL-4 receptor alpha (IL-4Rα) in macrophages.
- Examined responses in ovalbumin- and house dust mite-induced allergic airway disease models.
- Assessed airway hyperreactivity, inflammatory cell infiltration, mucus production, and collagen deposition.
Main Results:
- Depletion of IL-4Rα in macrophages reduced AAM markers but did not significantly decrease airway hyperreactivity, T(H)2 responses, mucus, eosinophils, or collagen.
- Both genetically modified mice and controls exhibited similar disease severity in acute and chronic models.
- No significant difference in disease outcomes was observed between LysM(cre)IL-4Rα(-/lox) mice and controls.
Conclusions:
- The presence of AAMs in allergic airway disease may be correlational rather than causal.
- IL-4Rα-dependent AAMs do not appear to play a critical role in the pathology of allergic airway disease.
- Findings suggest AAMs are a consequence of, not a driver of, disease pathogenesis.
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