| First Author | Hurdayal R | Year | 2013 |
| Journal | PLoS Pathog | Volume | 9 |
| Issue | 10 | Pages | e1003699 |
| PubMed ID | 24204259 | Mgi Jnum | J:247294 |
| Mgi Id | MGI:5917030 | Doi | 10.1371/journal.ppat.1003699 |
| Citation | Hurdayal R, et al. (2013) Deletion of IL-4 receptor alpha on dendritic cells renders BALB/c mice hypersusceptible to Leishmania major infection. PLoS Pathog 9(10):e1003699 |
| abstractText | In BALB/c mice, susceptibility to infection with the intracellular parasite Leishmania major is driven largely by the development of T helper 2 (Th2) responses and the production of interleukin (IL)-4 and IL-13, which share a common receptor subunit, the IL-4 receptor alpha chain (IL-4Ralpha). While IL-4 is the main inducer of Th2 responses, paradoxically, it has been shown that exogenously administered IL-4 can promote dendritic cell (DC) IL-12 production and enhance Th1 development if given early during infection. To further investigate the relevance of biological quantities of IL-4 acting on DCs during in vivo infection, DC specific IL-4Ralpha deficient (CD11c(cre)IL-4Ralpha(-/lox)) BALB/c mice were generated by gene targeting and site-specific recombination using the cre/loxP system under control of the cd11c locus. DNA, protein, and functional characterization showed abrogated IL-4Ralpha expression on dendritic cells and alveolar macrophages in CD11c(cre)IL-4Ralpha(-/lox) mice. Following infection with L. major, CD11c(cre)IL-4Ralpha(-/lox) mice became hypersusceptible to disease, presenting earlier and increased footpad swelling, necrosis and parasite burdens, upregulated Th2 cytokine responses and increased type 2 antibody production as well as impaired classical activation of macrophages. Hypersusceptibility in CD11c(cre)IL-4Ralpha(-/lox) mice was accompanied by a striking increase in parasite burdens in peripheral organs such as the spleen, liver, and even the brain. DCs showed increased parasite loads in CD11c(cre)IL-4Ralpha(-/lox) mice and reduced iNOS production. IL-4Ralpha-deficient DCs produced reduced IL-12 but increased IL-10 due to impaired DC instruction, with increased mRNA expression of IL-23p19 and activin A, cytokines previously implicated in promoting Th2 responses. Together, these data demonstrate that abrogation of IL-4Ralpha signaling on DCs is severely detrimental to the host, leading to rapid disease progression, and increased survival of parasites in infected DCs due to reduced killing effector functions. |
