IFN-γ-Dependent Recruitment of CD4⁺T Cells and Macrophages Contributes to Pathogenesis DuringLeishmania amazonensisInfection

Abstract

Interferon gamma (IFN-γ) is a key factor in the protection of hosts against intracellular parasites. This cytokine induces parasite killing through nitric oxide and reactive oxygen species production by phagocytes. Surprisingly, during Leishmania amazonensis infection, IFN-γ plays controversial roles. During in vitro infections, IFN-γ induces the proliferation of the amastigote forms of L. amazonensis. However, this cytokine is not essential at the beginning of an in vivo infection. It is not clear why IFN-γ does not mediate protection during the early stages of infection. Thus, the aim of our study was to investigate the role of IFN-γ during L. amazonensis infection. We infected IFN-γ(-/-) mice in the footpad and followed the development of leishmaniasis in these mice compared with that in WT mice. CD4(+) T lymphocytes and macrophages migrated earlier to the site of infection in the WT mice, and the earlier migration of these 2 cell types was associated with lesion development and parasite growth, respectively. These differences in the infiltrate populations were explained by the increased expression of chemokines in the lesions of the WT mice. Thus, we propose that IFN-γ plays a dual role during L. amazonensis infection; it is an important inducer of effector mechanisms, particularly through inducible nitric oxide synthase expression, and conversely, it is a mediator of inflammation and pathogenesis through the induction of the expression of chemokines. Our data provided evidence for a pathogenic effect of IFN-γ production during leishmaniasis that was previously unknown.

Impact of reactive oxygen species (ROS) on the control of parasite loads and inflammation in Leishmania amazonensis infection

“…We observed increase in paw swelling of infected WT mice until week 7 post-infection, followed by a slight decrease and lesion stabilization after this time point. Indeed, our results are supported by other works showing similar lesion kinetics during L. amazonensis infection in C57BL6 mice [ 42 – 44 ]. A role for IFN-γ and iNOS in this partial resistance to the parasite is clear, especially at later times of infection, since L. amazonensis- infected IFN-γ −/− and iNOS −/− mice develop larger non-healing lesions than wild type mice [ 44 , 45 ].…”

“…Indeed, our results are supported by other works showing similar lesion kinetics during L. amazonensis infection in C57BL6 mice [ 42 – 44 ]. A role for IFN-γ and iNOS in this partial resistance to the parasite is clear, especially at later times of infection, since L. amazonensis- infected IFN-γ −/− and iNOS −/− mice develop larger non-healing lesions than wild type mice [ 44 , 45 ]. ROS have been shown to play a role in the containment of metastasis to spleen and lymph nodes in experimental L. major infection [ 30 ].…”

The Effect of Ursolic Acid on Leishmania (Leishmania) amazonensis Is Related to Programed Cell Death and Presents Therapeutic Potential in Experimental Cutaneous Leishmaniasis

“…(L . ) amazonensis infection [ 54 , 55 , 56 ]. In addition, NO can be triggered by different stimuli as well as natural compounds from plants [ 57 ].…”

Modulation of Cytokines and Extracellular Matrix Proteins Expression by Leishmania amazonensis in Susceptible and Resistant Mice

“…Although Th1 response is required to induce lesion healing in CL caused by L. major in humans and mice ( Kane and Mosser, 2001 ; Murray et al, 2002 ; Trinchieri et al, 2003 ), excessive proinflammatory cytokines, mainly IFN-γ and TNF-α, can contribute to development of mucosal leishmaniasis (LM) ( Follador et al, 2002 ) and to the tissue damage ( Ribeiro-de-Jesus et al, 1998 ) produced by cellular recruitment, as observed in infections caused by L. braziliensis ( Vargas-Inchaustegui et al, 2010 ) and L. amazonensis ( Carneiro et al, 2015 ). Studies conducted in mock-treated C57BL/6 L. amazonensis -infected mice showed an excessive secretion of pro-inflammatory cytokines in these animals, leading to uncontrolled tissue degradation and perpetuates the non-healing condition ( Almeida-Souza et al, 2016 ).…”