2,3,7,8-Tetrachlorodibenzo-p-dioxin Slows the Progression of Experimental Cutaneous Leishmaniasis in Susceptible BALB/c and SCID Mice

Abstract

In a model of experimental cutaneous leishmaniasis, pre-exposure of Leishmania major-resistant mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor agonist, causes suppression of the protective anti-parasite T helper 1 response while paradoxically also reducing parasite burdens in those animals. In this study, we examined if TCDD exposure could also reduce parasite burdens in L. major-susceptible BALB/c mice. In the highest dose group (160 µg/Kg), TCDD treatment caused a significant reduction of parasite burdens by 10-fold after three weeks while also causing a significant lymphoid atrophy indicating suppression of the non-protective T helper 2 response. A dose-dependent delay of foot lesion progression was also observed such that lesion size in the highest dose group was less than half that of controls after 35 days of infection. Importantly, although TCDD exposure initially reduced disease severity and prolonged the course of disease by as much as three fold in some animals, this effect was transitory and TCDD did not induce resistance to L. major infection. Because TCDD exposure reduced L. major burdens in both resistant and susceptible mice, we hypothesized that TCDD reduces L. major burdens in mice by a mechanism that does not involve adaptive immunity. To test this, severe combined immunodeficient (SCID) mice were used. In mice infected with a moderate number of L. major (10,000), TCDD treatment caused a time- and dose-dependent decrease of parasite burdens by nearly 100-fold after six weeks in the highest dose group (200 µg/Kg). A significant and dose-dependent delay of foot lesion progression was also observed in these animals. These results indicate that TCDD exposure can reduce the severity of leishmanial disease in mice independent of adaptive immunity.

Role of Aryl Hydrocarbon Receptor (AhR) in the Regulation of Immunity and Immunopathology During Trypanosoma cruzi Infection

“…Decrease host resistance to a variety of infectious agents has been reported when TCDD exposure occurs prior to infection, however, whether the AhR ligation contributes to improve or worsen host resistant depends on the pathogen (48). Thus, in contrast to what is observed for T. cruzi infection, AhR activation by TCDD in Leishmania major infection reduces the parasite burden (57, 58).…”

Aryl Hydrocarbon Receptor-Signaling Regulates Early Leishmania major-Induced Cytokine Expression

“…Therefore, and because AhR has recently been identified as an important regulator of innate immunity (22, 26, 32–34) and was implicated in regulation of resistance to experimental leishmaniasis (24, 35, 36), we focused on AhR.…”

“…AhR is emerging as an important regulator in host defense and homeostasis [for a review, see (43)]. It was also recently described as a regulator in macrophage polarization (26) and several publications have reported a role for AhR in resistance to experimental Leishmaniasis (24, 35, 36).…”

Transcriptomic Impact of IMA-08401, a Novel AHR Agonist Resembling Laquinimod, on Rat Liver

“…It should also be noted that classification of an agent regarding its effects on immune defense is not always straightforward. Although TCDD is a notorious immune suppressant, it protects mice against Streptococcus pneumoniae -induced mortality and reduces pulmonary bacterial burden; it also mitigates the severity of leishmania disease in mice, independent of adaptive immunity [65,66]. Furthermore, in the immune system AHR has been demonstrated to be capable of directing naïve CD4+ T cell differentiation into either proinflammatory Th17 cells or into anti-inflammatory Treg cells, with the dose (or dosing) and duration of AHR activation by high-affinity ligands being the primary drivers of the direction [67].…”