Abstract
Leishmania major (L. major) parasites are intracellular parasites belong to the Trypanosomatidae family and are the causative agent of cutaneous leishmaniasis. This disease affects approximately 1.5 million per year worldwide and there is currently no prophylactic vaccine available. L. major is transmitted by the bite of an infected sandfly and has been considered for decades now as a mouse model of choice to identify the factors implicated in T helper (Th)1 and Th2 polarization due to the natural resistance and susceptibility to infection of C57BL/6 and BALB/c mice, respectively. In this study, we refine the role of IL-12p40 cytokine, which is implicated the development of a protective Th1 response, and STAT6, a transcription factor involved in the signaling via detrimental interleukin (IL)-4 and IL-13 associated Th2 cytokines during L. major infection in the BALB/c model. In the absence of STAT6 and IL-12p40 signaling, double knockout (DKO) susceptible BALB/c mice displayed reduced footpad swelling and ulcerative lesion compared to IL-12p40−/− mice upon L. major infection. Hence, they expressed slower upregulation of keratinocyte markers implicated in the inhibition of wound healing, such as keratin 6a (Krt6a) and Krt16. This coincides with the presence of neutrophils displaying an altered phenotype characterized by a lower expression of surface markers Ly6C, CD11b, and Ly6G. These neutrophils exhibited very lower levels of apoptosis similarly to neutrophils present in resistant STAT6−/− mice. Interestingly, the reduced footpad swelling in DKO mice is associated with a high footpad parasite level similar to susceptible IL-12p40−/− mice. In conclusion, this study demonstrate that in the absence of both STAT6 and IL-12p40 signaling, L. major-infected mice display smaller and less ulcerated lesions, which does, however, not correlate with reduced parasite load. In addition, the presence of neutrophils with an altered phenotype is associated with reduced apoptosis and delayed immunopathologies, demonstrating the detrimental role of STAT6 in infected susceptible BALB/c mice.
Highlights
Leishmaniasis is a neglected tropical disease caused by the bite of Leishmania-infected phlebotomine sandflies which affects both humans and animals
We have investigated the combined effect of the absence of the Th1-associated IL-12p40 and of the Th2-associated STAT6 proteins on the immunopathology and neutrophil phenotype generated during L. major IR75 infection in the susceptible BALB/c mice model
Upon infection with L. major IR75, STAT6−/− BALB/c mice developed small lesion, as could be expected from previous reports on murine cutaneous leishmaniasis (CL) [20, 21]. This result confirms the observation that BALB/c mice are able to mount a protective IFN-γ response upon L. major infection when given recombinant IL-12 [30, 31], but are unable to do so due to the inhibitory effect of STAT6
Summary
Leishmaniasis is a neglected tropical disease caused by the bite of Leishmania-infected phlebotomine sandflies which affects both humans and animals. Leishmania major causes the cutaneous form of the disease, mostly infects humans in the Middle East and has been used extensively in murine models. Susceptibility to murine L. major infections is related to an IL-4/IL-13-induced Th2 response which causes disease and can be fatal [1]. This Th1/ Th2 dichotomy model has been challenged by the discovery of other immune players, such as Th17, Treg and Th19 cells, IL-10 and B cells, playing a role in resistance/susceptibility to L. major infection [2]
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