Abrogation of IL-4 receptor-α-dependent alternatively activated macrophages is sufficient to confer resistance against pulmonary cryptococcosis despite an ongoing T_h2 response

 Authors

Abstract

In the murine model of pulmonary infection with Cryptococcus neoformans, IL-4 receptor α (IL-4Rα)-dependent polyfunctional T_h2 cells induce disease progression associated with alternative activation of lung macrophages. To characterize the effector role of IL-4Rα-dependent alternatively activated macrophages (aaMph), we intra-nasally infected mice with genetically ablated IL-4Rα expression on macrophages (LysM^CreIL-4Rα^–/lox mice) and IL-4Rα^–/lox littermates. LysM^CreIL-4Rα^–/lox mice were significantly more resistant to pulmonary cryptococcosis with higher survival rates and lower lung burden than non-deficient heterozygous littermates. Infected LysM^CreIL-4Rα^–/lox mice had reduced but detectable numbers of aaMph expressing arginase-1, chitinase-like enzyme (YM1) and CD206. Similar pulmonary expression of inducible nitric oxide synthase was found in LysM^CreIL-4Rα^–/lox and IL-4Rα^–/lox control mice, but macrophages from LysM^CreIL-4Rα^–/lox mice showed a higher potential to produce nitric oxide. In contrast to the differences in the macrophage phenotype, pulmonary T_h2 responses were similar in infected LysM^CreIL-4Rα^–/lox and IL-4Rα^–/lox mice with each mouse strain harboring polyfunctional T_h2 cells. Consistently, type 2 pulmonary allergic inflammation associated with eosinophil recruitment and epithelial mucus production was present in lungs of both LysM^CreIL-4Rα^–/lox and IL-4Rα^–/lox mice. Our results demonstrate that, despite residual IL-4Rα-independent alternative macrophage activation and ongoing T_h2-dependent allergic inflammation, abrogation of IL-4Rα-dependent aaMph is sufficient to confer resistance in pulmonary cryptococcosis. This is even evident on a relatively resistant heterozygous IL-4Rα^+/– background indicating a key contribution of macrophage IL-4Rα expression to susceptibility in allergic bronchopulmonary mycosis.

Keywords:

Key words

• cytokine receptor
 
• infection
 
• macrophage
 
• pulmonary cryptococcosis

• © The Japanese Society for Immunology. 2013. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Search this journal:

 

Advanced »

1. Int. Immunol. (2013) 25 (8): 459-470. doi: 10.1093/intimm/dxt003 First published online: March 26, 2013

1. » Abstract
2. Full Text (HTML)
3. Full Text (PDF)
4. All Versions of this Article:

   1. dxt003v1
   2. 25/8/459 most recent

• Email me this article