Abstract
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-4Rα). 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-4Rα deficient (CD11ccreIL-4Rα-/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-4Rα expression on dendritic cells and alveolar macrophages in CD11ccreIL-4Rα-/lox mice. Following infection with L. major, CD11ccreIL-4Rα-/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 CD11ccreIL-4Rα-/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 CD11ccreIL-4Rα-/lox mice and reduced iNOS production. IL-4Rα-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-4Rα 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.
Highlights
Leishmania spp. are protozoan parasites that are transmitted by Phlebotomus spp. sandflies and can cause several forms of disease in humans, ranging from localized cutaneous lesions to visceral Leishmaniasis, where parasites invade internal organs such as the spleen and liver
Mouse models of Leishmania major infection have demonstrated that a ‘‘healing’’ response in C57BL/6 mice requires the secretion of protective T helper (Th) 1 cytokines, including IFN-c, which mediates parasite killing by inducing nitric oxide production
‘‘non-healer’’ BALB/c mice are unable to control infection and develop a T helper 2 (Th2) immune response characterized by the production of IL-4 and IL-13 cytokines
Summary
Leishmania spp. are protozoan parasites that are transmitted by Phlebotomus spp. sandflies and can cause several forms of disease in humans, ranging from localized cutaneous lesions to visceral Leishmaniasis, where parasites invade internal organs such as the spleen and liver. Susceptible BALB/c mice show progressive lesion development with dissemination of parasites to visceral organs, while resistant C57BL/6 mice are able to control infection and heal lesions [2,3,4]. IL-4 and IL-13, both of which signal through a common receptor chain, the IL-4 receptor alpha (IL4Ra) are known to be important susceptibility factors in L. major infection [3,6,8,15,16]. Both BALB/c and C57BL/6 mice secrete IL-4 early after infection production of IL-4 is sustained in susceptible BALB/c mice and transient in resistant C57BL/6
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