Abstract
BackgroundDuring infection with Leishmania donovani, parasite control is linked to the systemic Th1 immune response, but in infected organs (liver, spleen and bone marrow), the response differs according to the micro-environment. The pleiomorphic cytokine interleukin-33 (IL-33) exerts various roles during infection, either protective or detrimental. In this study, we explored the role of IL-33 in the outcome of Leishmania infection in the spleen.MethodsWe used several mouse models, on BALB/c and C57BL/6 (B6) backgrounds, infected with L. donovani and sacrificed at 15, 30 or 60 days after infection and characterized mRNA expression of immune markers, immune cell populations, histological response, and parasite loads.ResultsDuring infection IL-33 and ST2 mRNA increased in parallel in the spleen of wild type (wt) animals and paralleled the immunodetection of ST2+ and IL-33+ cells; their expression was twice as high in BALB/c, compared to B6 mice. Mice treated with twice-weekly injections of rIL-33 had higher splenic parasite burdens on D15 (BALB/c) or on D60 (B6). In BALB/c, IL-33 treatment led to immune exhaustion with abolition of Th1 cytokine expression (IFN-γ and IL-12) in the spleen and higher serum levels of Th2 cytokines (IL-4, IL-5 and IL-13). In B6, IL-33 treatment induced the Treg cell pathway with a dramatic increase of FoxP3 mRNA induction and expression on tissue sections. IL-33-KO mice had lower parasite loads and a higher Th1 response than their wt counterparts.ConclusionsIL-33 appears as a factor of aggravation of the disease in the spleen tissue of mice infected with L. donovani.
Highlights
During infection with Leishmania donovani, parasite control is linked to the systemic Th1 immune response, but in infected organs, the response differs according to the micro-envi‐ ronment
IL‐33 and its receptor ST2 are more expressed in the spleen of susceptible BALB/c mice, compared to C57BL/6 mice the expression of IL-33 mRNA was roughly similar in both mouse strains at baseline, it increased earlier in BALB/c, and twice as much in BALB/c as in C57BL/6 (B6) mice (ANOVA: F(1, 51) = 16.97, P < 0.001 and P < 0.01 at day 15 and day 30, respectively) (Fig. 1a, b)
Immunohistochemical staining of spleen tissue using an IL-33 antibody confirmed that IL-33 expressing cells were present in higher amounts in BALB/c mice than in BALB/c and C57BL/6 (B6) mice, on Day 15 and Day 30 (Fig. 1c)
Summary
During infection with Leishmania donovani, parasite control is linked to the systemic Th1 immune response, but in infected organs (liver, spleen and bone marrow), the response differs according to the micro-envi‐ ronment. Infection control is known to be linked to an efficient Th1 immune response, while a Th2 response is associated to progression of disease. Our team has previously reported elevated concentrations of IL-33 in the serum of patients infected with L. infantum, and showed in a mouse model of L. donovani infection, that IL-33 was associated with poorer control of infection in the liver [5]. The aim of this study was to characterize the impact of IL-33 on the splenic tissue response during VL, using various mouse models to better understand the effects of this inflammatory cytokine known to have contrasting effects according to patient background and disease [6, 8, 9]
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