Targeting IL-27 and/or IL-10 in Experimental Murine Visceral Leishmaniasis.
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ABSTRACT:
SUBMITTER: Murray HW
PROVIDER: S-EPMC7646755 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The relationship established between Leishmania infantum and the vertebrate host can lead to a self-healing infection or to the manifestation of visceral leishmaniasis, a chronic systemic infection associated with high rates of mortality. We hypothesized that regulatory cytokines, such as interleukin-27 (IL-27), play a role in susceptibility to L. infantum infection. IL-27 is a heterodimeric cytokine composed of IL-27p28 and EBi3 subunits which, when combined, bind to IL-27R, leading to STAT-1 and -3 activation, playing a role in the regulation of the immune response. We observed in this work that IL-27 regulates the Th1/Th17 profiles in a mouse model of visceral leishmaniasis (VL) caused by L. infantum We showed here that the pathogen recognition by endosomal Toll-like receptors triggers a type I interferon (IFN) response, which acts through the type I IFN receptor and interferon regulatory factor 1 to induce IL-27 production by macrophages. Furthermore, IL-27 plays a major regulatory role in vivo, because Ebi3(-/-) mice can efficiently control parasite replication despite reduced levels of IFN-γ compared to wild-type mice. On the other hand, the absence of Ebi3 leads to exacerbated IL-17A production in the infected organs as well as in a coculture system, suggesting a direct regulatory action of IL-27 during L. infantum infection. As a consequence of exacerbated IL-17A in Ebi3(-/-) mice, a greater neutrophil influx was observed in the target organs, playing a role in parasite control. Thus, this work unveiled the molecular steps of IL-27 production after L. infantum infection and demonstrated its regulatory role in the IL-17A-neutrophil axis.
| S-EPMC4962641 | biostudies-literature
Project description:Background: Visceral leishmaniasis (VL) is caused by Leishmania infantum or L. donovani infection. One of the main problems related to this disease is the emergence of severe clinical forms with a lethality of 5-20%, even while under specific treatment. In humans and other species susceptible to fatal VL, such as dogs and hamsters, the disruption of splenic white pulp (WP) is accompanied by disease progression. Control of VL progression is seen in BALB/c mice, as evidenced by a mild clinical presentation and controlled parasite replication in the liver and spleen. In this study, we investigated the features involved in the morphological remodeling of splenic compartments associated with the control of VL progression to death. Methods: We evaluated cohorts of BALB/c mice after 30, 60, and 90 days of infection by L. infantum. Spleen morphology, cell population subsets and cytokine production were studied in the spleen using flow- and histo-cytometry. Results: Intraperitoneal infection with 108 promastigotes of L. infantum led to progressive increases in spleen size at 60 and 90 days after infection. Splenomegaly was the only clinical sign of disease observed. At 30 days after infection, hyperplasia in the WP and decreased numbers of plasmacytoid dendritic cells were observed. The WP hyperplasia subsided at 60 days post-infection. However, the splenomegaly remained in association with increased numbers of macrophages, B and T lymphocytes and plasma cells. An increased number of lymphoid tissue inducer (LTi) cells was observed; these were distributed around the periarteriolar lymphoid sheath in control mice and scattered throughout the red pulp in the Leishmania-infected mice. After 90 days of infection, increased IL-6 and IFN-? production was seen in the spleen, as well as higher frequencies of follicular and plasmacytoid dendritic cells. Conclusion: The data presented herein emphasizes the potential role of spleen remodeling in the control of severe forms of VL and highlights features potentially involved in this process.
| S-EPMC7174685 | biostudies-literature
Project description:BackgroundVisceral leishmaniasis (VL) is a severe disease caused by infection with protozoa of the genus Leishmania. Classic VL is characterized by a systemic infection of phagocytic cells and an intense activation of the inflammatory response. It is unclear why 90% of infected individuals do not develop the disease while a minority develop the classical form. Furthermore, among those that develop disease, a small group progresses to more severe form that is unresponsive to treatment. The presence of inflammatory mediators in serum could theoretically help to control the infection. However, there is also a release of anti-inflammatory mediators that could interfere with the control of parasite multiplication. In this study, we took advantage of the spectrum of outcomes to test the hypothesis that the immune profile of individuals infected with Leishmania (L.) infantum is associated with the development and severity of disease.Methodology/principal findingsSera from patients with confirmed diagnosis of VL were evaluated for the presence of numerous molecules, and levels compared with healthy control and asymptomatic infected individuals.Conclusions/principal findingsAlthough differences were not observed in LPS levels, higher levels of sCD14 were detected in VL patients. Our data suggest that L. infantum may activate the inflammatory response via CD14, stimulating a generalized inflammatory response with production of several cytokines and soluble molecules, including IFN-?, IL-27, IL-10, IL-6 and sCD14. These molecules were strongly associated with hepatosplenomegaly, neutropenia and thrombocytopenia. We also observed that IL-6 levels greater than 200 pg/ml were strongly associated with death. Together our data reinforce the close relationship of IFN-?, IL-10, IL-6, TNF-? and IL-27 in the immune dynamics of VL and suggest the direct participation of sCD14 in the activation of the immune response against L. infantum.
| S-EPMC4729473 | biostudies-literature
Project description:BACKGROUND: Immune responses play critical roles in the leishmaniasis eradication. IL-10 is a key regulator of immune responses, and the polymorphisms within its promoter region are associated with alteration in its expression. Therefore, this study was designed to examine the correlation between polymorphism at the -1082 position of the IL-10 gene and visceral leishmaniasis (VL). METHODS: The IL-10 -1082 polymorphism and anti-Leishmania antibody titration were examined in 110 patients with clinical presentation of VL and seropositive for the Leishmania (group 1), 74 seropositive patients but without clinical presentation (group 2) and 113 healthy controls (group 3) using the PCR-RFLP and immunofluorescence techniques, respectively. RESULTS: The polymorphism at IL-10 -1082 (A/G) position was significantly associated with VL and A/G genotype was significantly higher in VL patients when compared to the groups 2 and 3 (P< 0.001). However, the results demonstrated that the A and G alleles were not associated with VL (P= 0.263). CONCLUSIONS: Previous investigations have shown that the polymorphism at the -1082 position of the IL-10 gene can influence its expression and also it has been proved that IL-10 level was increased during VL. Our results suggest that the A/G genotype may be considered as a risk factor for VL.
| S-EPMC4411907 | biostudies-other
Project description:Transcriptional analysis of complex biological scenarios has been used extensively, even though sometimes the results of such analysis may prove imprecise or difficult to interpret due to an overwhelming amount of information. In this study, a large-scale real-time qPCR experiment was coupled to multivariate statistical analysis in order to describe the main immunological events underlying the early L. infantum infection in livers of BALB/c mice. High-throughput qPCR was used to evaluate the expression of 223 genes related to immunological response and metabolism 1, 3, 5, and 10 days post infection. This integrative analysis showed strikingly different gene signatures at 1 and 10 days post infection, revealing the progression of infection in the experimental model based on the upregulation of particular immunological response patterns and mediators. The gene signature 1 day post infection was not only characterized by the upregulation of mediators involved in interferon signaling and cell chemotaxis, but also the upregulation of some inhibitory markers. In contrast, at 10 days post infection, the upregulation of many inflammatory and Th1 markers characterized a more defined gene signature with the upregulation of mediators in the IL-12 signaling pathway. Our results reveal a significant connection between the expression of innate immune response and metabolic and inhibitory markers in early L. infantum infection of the liver.
2021-07-12 | GSE159195 | GEO
Project description:Interleukin 27 (IL-27) plays diverse immune regulatory roles in autoimmune disorders and promotes the generation of IL-10-producing CD4+ T cells characterized by producing the immunosuppressive cytokine IL-10. However, whether IL-27 participates in pathological progress of Sjögren syndrome (SS) through regulating CD4+IL-10+ T cells remains unknown. Here we aimed to explore the potential role of IL-27 and CD4+IL-10+ T cells in the pathogenesis of SS. The IL-27 gene knockout non-obese diabetic (Il-27 -/-NOD) mice were generated and injected with exogenous IL-27. Exogenous injection of IL-27 and neutralization of IL-27 with anti-IL-27 antibody in NOD mice were performed. The histopathologic changes in submandibular glands, lacrimal glands and lung, salivary flow rate, and percentages of CD4+IL-10+ T cells were determined. And, ovalbumin-immunized C57L/B6 mice were injected with IL-27 to detect the percentage of CD4+IL-10+ T cells. In vitro, splenic naive T cells from C57L/B6 mice were cultured with IL-27 for 4 days to induce the differentiation of CD4+IL-10+ T cells. In addition, IL-27, IL-10, and CD4+IL-10+ T cells were determined in health control and SS patients. The results showed that Il-27 -/-NOD mice had more severe disease and lower level of CD4+IL-10+ T cells than control mice. And IL-27 promoted the generation and differentiation of CD4+IL-10+ T cells in vivo and in vitro significantly. In agreement with the findings in the SS-like mice, patients with SS showed lower levels of IL-27, IL-10, and CD4+IL-10+ T cells. Our findings indicated that IL-27 deficiency aggravated SS by regulating CD4+IL-10+ T cells. Targeting IL-27 and CD4+IL-10+ T cells may be a novel therapy for patients with SS.
| S-EPMC7431603 | biostudies-literature
Project description:IL-10 is elevated in the autoimmune disease systemic lupus erythematosus (SLE). Here, we show that conventional dendritic cells (cDCs) from predisease lupus-prone B6.NZM Sle1/Sle2/Sle3 triple congenic (TCSle) mice produce more IL-10 than wild-type congenic cDCs upon TLR stimulation, and this overproduction is prevented by blocking the type I IFN receptor (IFNAR) with specific Abs. Priming wild-type cDCs with type I IFN mimics the IL-10 overproduction of TCSle cDCs. The MAPK ERK is more phosphorylated in lupus cDCs, partially contributing to IL-10 overproduction. Moreover, we found that TCSle cDCs express higher levels of IL-27 upon TLR7/TLR9 stimulation, and IFNAR blockade reduced IL-27 levels in TCSle cDCs. These results suggest that dysregulated type I IFNs in cDCs contribute to the increased IL-10 and IL-27 in SLE. Since IL-27 neutralization did not inhibit TLR-induced IL-10 production, we propose that type I IFNs enhanced IL-10 in TCSle cDCs independently from IL-27. Moreover, RNA sequencing analysis of a cohort of SLE patients reveals higher gene expression of these cytokines in SLE patients expressing a high IFN signature. Since IL-27 and IL-10 have both pro- and anti-inflammatory effects, our results also suggest that these cytokines can be modulated by the therapeutic IFN blockade in trials in SLE patients and have complex effects on the autoimmune response.
| S-EPMC7901002 | biostudies-literature
Project description:Hemophagocytosis is a phenomenon in which macrophages phagocytose blood cells. There are reports on up-regulated hemophagocytosis in patients with infectious diseases including typhoid fever, tuberculosis, influenza and visceral leishmaniasis (VL). However, mechanisms of infection-associated hemophagocytosis remained elusive due to a lack of appropriate animal models. Here, we have established a mouse model of VL with hemophagocytosis. At 24 weeks after infection with 1 x 10(7) Leishmania donovani promastigotes, BALB/cA mice exhibited splenomegaly with an average tissue weight per body weight of 2.96%. In the tissues, 28.6% of macrophages contained phagocytosed erythrocytes. All of the hemophagocytosing macrophages were parasitized by L. donovani, and higher levels of hemophagocytosis was observed in heavily infected cells. Furthermore, more than half of these hemophagocytes had two or more macrophage-derived nuclei, whereas only 15.0% of splenic macrophages were bi- or multi-nuclear. These results suggest that direct infection by L. donovani causes hyper-activation of host macrophages to engulf blood cells. To our knowledge, this is the first report on hemophagocytosis in experimental Leishmania infections and may be useful for further understanding of the pathogenesis.
| S-EPMC4778860 | biostudies-literature
Project description:Transcriptional analysis of complex biological scenarios has been used extensively, even though sometimes the results of such analysis may prove imprecise or difficult to interpret due to an overwhelming amount of information. In this study, a large-scale real-time qPCR experiment was coupled to multivariate statistical analysis in order to describe the main immunological events underlying the early L. infantum infection in livers of BALB/c mice. High-throughput qPCR was used to evaluate the expression of 223 genes related to immunological response and metabolism 1, 3, 5, and 10 days post infection. This integrative analysis showed strikingly different gene signatures at 1 and 10 days post infection, revealing the progression of infection in the experimental model based on the upregulation of particular immunological response patterns and mediators. The gene signature 1 day post infection was not only characterized by the upregulation of mediators involved in interferon signaling and cell chemotaxis, but also the upregulation of some inhibitory markers. In contrast, at 10 days post infection, the upregulation of many inflammatory and Th1 markers characterized a more defined gene signature with the upregulation of mediators in the IL-12 signaling pathway. Our results reveal a significant connection between the expression of innate immune response and metabolic and inhibitory markers in early L. infantum infection of the liver.
| S-EPMC8267970 | biostudies-literature
Project description:During visceral leishmaniasis (VL), Th1-based inflammation is induced to control intracellular parasites. Inflammation-based pathology was shown to be dampened by IL-10 and eventual programmed death 1-mediated T cell exhaustion. Cell type(s) responsible for the initiation of T cell-produced IL-10 during VL are unknown. CD19(+), CD5(-), CD1d(-), IgD(hi) regulatory B cells from healthy controls produced IL-10 in the absence of infection or stimulation, in contrast to IgD(lo/neg) B cells. IgD(hi) B cells may have a de novo versus induced regulatory program. The population of IgD(hi) B cells increased 3-fold as VL progressed. B cells from VL dogs were necessary and sufficient to suppress Th1 cell effector function. IgD(hi) B cells induced IL-10 production by T cells and IgD(lo) B cells. Blockage of B cell-specific PD-L1 restored Th1 responses. IgD(hi) regulatory B cells represent a novel regulatory B cell that may precipitate T cell exhaustion during VL.
| S-EPMC4868652 | biostudies-literature