Abstract
IL-4 and IL-13 cytokines have been associated with a non-healing phenotype in murine leishmaniasis in L. mexicana -infected BALB/c mice as demonstrated in IL-4−/−, IL-13−/− and IL-4Rα-/- global knockout mouse studies. However, it is unclear from the studies which cell-type-specific IL-4/IL-13 signaling mediates protection to L. mexicana. Previous studies have ruled out a role for IL-4-mediated protection on CD4+ T cells during L. mexicana infections. A candidate for this role may be non-lymphocyte cells, particularly DCs, as was previously shown in L. major infections, where IL-4 production drives dendritic cell-IL-12 production thereby mediating a type 1 immune response. However, it is unclear if this IL-4-instruction of type 1 immunity also occurs in CL caused by L. mexicana, since the outcome of cutaneous leishmaniasis often depends on the infecting Leishmania species. Thus, BALB/c mice with cell-specific deletion of the IL-4Rα on CD11c+ DCs (CD11ccreIL-4Rα-/lox) were infected with L. mexicana promastigotes in the footpad and the clinical phenotype, humoral and cellular immune responses were investigated, compared to the littermate control. Our results show that CL disease progression in BALB/c mice is independent of IL-4Rα signaling on DCs as CD11ccreIL-4Rα-/lox mice had similar footpad lesion progression, parasite loads, humoral responses (IgE, IgG1, IgG 2a/b), and IFN-γ cytokine secretion in comparison to littermate controls. Despite this comparable phenotype, surprisingly, IL-4 production in CD11ccreIL-4Rα-/lox mice was significantly increased with an increasing trend of IL-13 when compared to littermate controls. Moreover, the absence of IL-4Rα signaling did not significantly alter the frequency of CD4 and CD8 lymphocytes nor their activation, or memory phenotype compared to littermate controls. However, these populations were significantly increased in CD11ccreIL-4Rα-/lox mice due to greater total cell infiltration into the lymph node. A similar trend was observed for B cells whereas the recruitment of myeloid populations (macrophages, DCs, neutrophils, and Mo-DCs) into LN was comparable to littermate IL-4Rα-/lox mice. Interestingly, IL-4Rα-deficient bone marrow-derived dendritic cells (BMDCs), stimulated with LPS or L. mexicana promastigotes in presence of IL-4, showed similar levels of IL-12p70 and IL-10 to littermate controls highlighting that IL-4-mediated DC instruction was not impaired in response to L. mexicana. Similarly, IL-4 stimulation did not affect the maturation or activation of IL-4Rα-deficient BMDCs during L. mexicana infection nor their effector functions in production of nitrite and arginine-derived metabolite (urea). Together, this study suggests that IL-4 Rα signaling on DCs is not key in the regulation of immune-mediated protection in mice against L. mexicana infection.
Highlights
Leishmaniases are classified as neglected tropical diseases [1, 2] that are caused by Leishmania spp; a vector-borne intracellular trypanosomatid protozoan parasite
Female CD11ccreIL-4Ra-/lox showed fulminant cutaneous leishmaniasis characterized by increasing footpad swelling similar to IL-4Ra-/lox littermate control BALB/c mice during the 8week period (Figure 1A)
Female BALB/c mice deficient for IL-4Ra on CD11c+ dendritic cells (DCs) had similar numbers of parasites in their lesions and popliteal lymph nodes (pLNs) compared to their littermate controls at week 8 post-infection (p.i) (Figure 1B)
Summary
Leishmaniases are classified as neglected tropical diseases [1, 2] that are caused by Leishmania spp; a vector-borne intracellular trypanosomatid protozoan parasite. This disease is characterized by a spectrum of clinical manifestations ranging from selfhealing skin lesions of localized cutaneous leishmaniasis, mucocutaneous leishmaniasis, diffuse cutaneous leishmaniasis, and visceral leishmaniasis depending on Leishmania parasite species and host immune response [3, 4]. A promising alternative is the use of chemoimmunotherapeutic approaches, which have the potential to increase efficacy and decrease the toxicity of antileishmanial drugs thereby extending their lifespan in clinical use [15] Central to this approach is the identification of correlates of immune protection in the host organism during active infection. To better understand the specific cell subsets in the host that render IL-4Ra-/- mice resistant to CL, recent studies have shown that deficiency of IL-4Ra signaling on CD4+ T cells protects mice from L. major infections but the protection is sex-dependent in
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