Leptin regulates Granzyme-A, PD-1 and CTLA-4 expression in T cell to control visceral leishmaniasis in BALB/c Mice

Alti Dayakar,Sambamurthy Chandrasekaran,Radheshyam Maurya,Jalaja Veronica,Vadloori Bharadwaja

doi:10.1038/s41598-017-15288-7

Alti Dayakar, Sambamurthy Chandrasekaran + Show 3 more

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https://doi.org/10.1038/s41598-017-15288-7

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Journal: Scientific Reports	Publication Date: Nov 7, 2017
Citations: 19	License type: open-access

Affiliation: University of Hyderabad

Abstract

Visceral leishmaniasis (VL) is responsible for several deaths in malnourished children accompanied by diminished circulating leptin and impaired cell-mediated immunity. Typically, leptin deficiency is associated with the Th2 polarization that markedly coincides with the pathogenesis of VL. The aim of the present study was to unravel the prophylactic role of leptin in malnutrition-coupled VL mice. Interestingly, we observed that L. donovani infection itself reduces the serum leptin levels in malnutrition. Exogenous leptin restored severe body weight loss and parasite load in the spleen and liver of malnourished infected mice compared to controls. Leptin increases functional CD8+ T-cell population, Granzyme-A expression down-regulates anergic T-cell markers such as PD-1 and CTLA-4. It was also noticed that, leptin suppresses GM-CSF mRNA expression in parasite favored monocytes and reduced arginase activity in bone marrow derived macrophage indicate macrophages dependent T-cell activation and proliferation. Leptin-induced IFN-γ, IL-2, and TNF-α cytokines in the culture supernatant of splenocytes upon soluble leishmanial antigen (SLA) stimulation and significantly up-regulates serum IgG2a titers, which help to generate Th1 immune response in VL. Furthermore, leptin induced a granulomatous response and restored L. donovani induced tissue degeneration in the liver. Altogether, our findings suggest the exogenous leptin can restore T cell mediated immunity in malnourished VL mice.

Highlights

Visceral Leishmaniasis (VL) is a vector borne infectious disease caused by the protozoan parasite Leishmania donovani in the Indian subcontinent
To follow up on our earlier report and to test if leptin administration could be protective in malnutrition coupled VL38, we investigated the effects of exogenous leptin in malnutrition coupled L. donovani infection in BALB/c mice
Visceral leishmaniasis (VL) is delineated by the inability to control L. donovani infection associated with an intense T-cell insensitivity to Leishmania antigens and production of IL-10 cytokine[54,55,56]

Summary

Introduction

Visceral Leishmaniasis (VL) is a vector borne infectious disease caused by the protozoan parasite Leishmania donovani in the Indian subcontinent. Malnutrition is associated with immune suppression thereby increasing the incidence of infections and mortality[16], which affects both innate and acquired immunity[17] It is associated with low circulating leptin levels[18]; thereby highly susceptible to infections due to defective cytokine production[19]. Previous studies have been reported that the systemic circulating leptin deficiency in malnutrition is correlated in several infectious diseases such as tuberculosis[26], pneumonia[27], sepsis[28], colitis[29], viral immunity[30] amoebiasis[31] and leishmaniasis[32,33] due to defective cytokine production[19,25]. Leptin induces the innate immune response in bone marrow derived antigen-presenting cells, resultant an increase of nitric oxide and proinflammatory cytokines (IFNγ, IL-12, and IL1β) response in SLA stimulated splenocytes[37]. The data presented here indicate that leptin supplementation may have positive effects in control of VL

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