SUMMARY Neutrophils are involved in the early stages of immune responses to pathogens. Here, we investigated the role of neutrophils during the establishment of Leishmania amazonensis infection in BALB/c and C57BL/6 mice. First, we showed an accumulation of neutrophils between 6 and 24 h post-infection, followed by a reduction in neutrophil numbers after 72 h. Next, we depleted neutrophils prior to infection using RB6-8C5 or 1A8 mAb. Neutrophil depletion led to faster lesion development, increased parasite numbers and higher arginase activity during the first week of infection in BALB/c mice, but not in C57BL/6 mice. Increased susceptibility was accompanied by augmented levels of anti-L. amazonensis IgG and increased production of IL-10 and IL-17. Because IL-10 is a mediator of susceptibility to Leishmania infection, we blocked IL-10 signalling in neutrophil-depleted mice using anti-IL-10R. Interestingly, inhibition of IL-10 signalling abrogated the increase in parasite loads observed in neutrophil-depleted mice, suggesting that parasite proliferation is at least partially mediated by IL-10. Additionally, we tested the effect of IL-17 in inflammatory macrophages and observed that IL-17 increased arginase activity and favoured parasite growth. Taken together, our data indicate that neutrophils control parasite numbers and limit lesion development during the first week of infection in BALB/c mice.
Nitric oxide (NO) and reactive oxygen species (ROS) are key molecules in resistance to pathogens. Little is known about their role in pathogenesis of periapical lesions. To address this issue, we induced periapical lesions in mice lacking nitric oxide synthase (iNOS(-/-)) or phagocyte oxidase (PHOX(-/-)). iNOS(-/-) mice expressed higher levels of IL-1β, TNF-α, RANK, RANKL, and MCP-1 than C57BL/6 and PHOX(-/-). Apical thickening of the periodontal ligament was also greater in iNOS(-/-) compared with other groups. Interestingly, ROS production did not interfere in periapical lesion progression, but seemed to be essential for the appearance of multinucleated TRAP-positive cells. Thus, periapical lesion progression in iNOS(-/-) was associated with an imbalance of pro-inflammatory cytokines (IL-1β and TNF-α), bone-resorptive modulators (RANK and RANKL), and MCP-1. We conclude that NO, but not ROS, controls progression of bone resorption in a murine experimental model of apical periodontitis.
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.
We have previously demonstrated that yangambin, a lignan obtained from Ocotea duckei Vattimo (Lauraceae), shows antileishmanial activity against promastigote forms of Leishmania chagasi and Leishmania amazonensis. The aim of this study was to determine the in vitro effects of yangambin against these parasites using electron and confocal microscopy. L. chagasi and L. amazonensis promastigotes were incubated respectively with 50 μg/mL and 65 μg/mL of pure yangambin and stained with acridine orange. Treated-parasites showed significant alterations in fluorescence emission pattern and cell morphology when compared with control cells, including the appearance of abnormal round-shaped cells, loss of cell motility, nuclear pyknosis, cytoplasm acidification and increased number of acidic vesicular organelles (AVOs), suggesting important physiological changes. Ultrastructural analysis of treated-promatigotes showed characteristics of cell death by apoptosis as well as by autophagy. The presence of parasites exhibiting multiples nuclei suggests that yangambin may also affect the microtubule dynamic in both Leishmania species. Taken together our results show that yangambin is a promising agent against Leishmania.
We evaluated the role of IL-18 during Leishmania amazonensis infection in C57BL/6 mice, using IL-18KO mice. We showed that IL-18 is involved in susceptibility to L. amazonensis, since IL-18KO mice presented reduced lesions and parasite loads. Because macrophages are the host cells of the parasite, we investigated if macrophages were involved in IL-18-mediated susceptibility to L. amazonensis. We showed that macrophages obtained from WT or IL-18KO responded similarly to L. amazonensis infection. Moreover, we showed that C57BL/6 macrophages do not respond to IL-18, since they do not express IL-18R. Therefore, macrophages are not involved in IL-18-mediated susceptibility to L. amazonensis.
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