| First Author | Müller U | Year | 2013 |
| Journal | Int Immunol | Volume | 25 |
| Issue | 8 | Pages | 459-70 |
| PubMed ID | 23532373 | Mgi Jnum | J:200178 |
| Mgi Id | MGI:5507760 | Doi | 10.1093/intimm/dxt003 |
| Citation | Muller U, et al. (2013) Abrogation of IL-4 receptor-alpha-dependent alternatively activated macrophages is sufficient to confer resistance against pulmonary cryptococcosis despite an ongoing T(h)2 response. Int Immunol 25(8):459-70 |
| abstractText | In the murine model of pulmonary infection with Cryptococcus neoformans, IL-4 receptor alpha (IL-4Ralpha)-dependent polyfunctional T(h)2 cells induce disease progression associated with alternative activation of lung macrophages. To characterize the effector role of IL-4Ralpha-dependent alternatively activated macrophages (aaMph), we intra-nasally infected mice with genetically ablated IL-4Ralpha expression on macrophages (LysM(Cre)IL-4Ralpha(-/lox) mice) and IL-4Ralpha(-/lox) littermates. LysM(Cre)IL-4Ralpha(-/lox) mice were significantly more resistant to pulmonary cryptococcosis with higher survival rates and lower lung burden than non-deficient heterozygous littermates. Infected LysM(Cre)IL-4Ralpha(-/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(Cre)IL-4Ralpha(-/lox) and IL-4Ralpha(-/lox) control mice, but macrophages from LysM(Cre)IL-4Ralpha(-/lox) mice showed a higher potential to produce nitric oxide. In contrast to the differences in the macrophage phenotype, pulmonary T(h)2 responses were similar in infected LysM(Cre)IL-4Ralpha(-/lox) and IL-4Ralpha(-/lox) mice with each mouse strain harboring polyfunctional T(h)2 cells. Consistently, type 2 pulmonary allergic inflammation associated with eosinophil recruitment and epithelial mucus production was present in lungs of both LysM(Cre)IL-4Ralpha(-/lox) and IL-4Ralpha(-/lox) mice. Our results demonstrate that, despite residual IL-4Ralpha-independent alternative macrophage activation and ongoing T(h)2-dependent allergic inflammation, abrogation of IL-4Ralpha-dependent aaMph is sufficient to confer resistance in pulmonary cryptococcosis. This is even evident on a relatively resistant heterozygous IL-4Ralpha(+/-) background indicating a key contribution of macrophage IL-4Ralpha expression to susceptibility in allergic bronchopulmonary mycosis. |
