IL-27 enhances Leishmania amazonensis infection via ds-RNA dependent kinase (PKR) and IL-10 signaling

Barreto-de-Souza, Victor; Ferreira, Pedro L C; Vivarini, Áislan de Carvalho; Calegari-Silva, Teresa Cristina; Soares, Deivid Costa; Regis, Eduardo G.; Pereira, Renata M.; Silva, Aristóbolo M.; Saraiva, Elvira M.; Lopes, Ulisses Gazos; Bou-Habib, Dumith Chequer

doi:10.1016/j.imbio.2014.11.006

Cited by 17 publications

(18 citation statements)

References 40 publications

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“…In contrast, IL-17 can promote progression of CL in susceptible mice (50). The parasite load in IL-27R −− mice infected with Leishmania major was not affected (51), whereas IL-27 has been shown to promote Leishmania amazonensis replication in macrophages (52). Interestingly, a recent study showed that IL-27 could mediate susceptibility of mice to L. infantum infections by suppressing IL-17 production by neutrophils (53).…”

Section: Discussionmentioning

confidence: 99%

Visceral Leishmaniasis Patients Display Altered Composition and Maturity of Neutrophils as well as Impaired Neutrophil Effector Functions

et al. 2016

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Immunologically, active visceral leishmaniasis (VL) is characterized by profound immunosuppression, severe systemic inflammatory responses, and an impaired capacity to control parasite replication. Neutrophils are highly versatile cells, which play a crucial role in the induction as well as the resolution of inflammation, the control of pathogen replication, and the regulation of immune responses. Neutrophil functions have been investigated in human cutaneous leishmaniasis; however, their role in human VL is poorly understood. In the present study we evaluated the activation status and effector functions of neutrophils in patients with active VL and after successful anti-leishmanial treatment. Our results show that neutrophils are highly activated and have degranulated; high levels of arginase, myeloperoxidase, and elastase, all contained in neutrophils’ granules, were found in the plasma of VL patients. In addition, we show that a large proportion of these cells are immature. We also analyzed effector functions of neutrophils that are essential for pathogen clearance and show that neutrophils have an impaired capacity to release neutrophil extracellular traps, produce reactive oxygen species, and phagocytose bacterial particles, but not Leishmania parasites. Our results suggest that impaired effector functions, increased activation, and immaturity of neutrophils play a key role in the pathogenesis of VL.

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Section: Discussionmentioning

confidence: 99%

Visceral Leishmaniasis Patients Display Altered Composition and Maturity of Neutrophils as well as Impaired Neutrophil Effector Functions

et al. 2016

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“…These results partially explain the higher parasite burdens quantified in the presence of IL-27. Addition of IL-27 in vitro exacerbates the infection of human macrophages by Leishmania amazonensis via IL-10 (11) and combined production of IL-27 and IL-10 by L. donovani -infected DCs is essential for IL-10 production by Th1 cells, resulting in parasite persistence (13). A recent work in EBI3 −/− mice suggested a role for IL-27 in controlling IL-17 production and neutrophil infiltration during the chronic phase of L. infantum infection (30).…”

Section: Discussionmentioning

confidence: 99%

“…In mice, IL-27 appears to be essential to prevent severe immunopathology after infection with both cutaneous (9) and visceral (10) strains, mainly through the effects of IL-10. However, whether IL-27 directly affects parasite burdens (9, 11) or if IL-10 appears as a consequence of inflammatory (7, 12) or suppressor (13) events is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-27 Early Impacts Leishmania infantum Infection in Mice and Correlates with Active Visceral Disease in Humans

et al. 2016

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The complexity of Leishmania–host interactions, one of the main leishmaniasis issues, is yet to be fully understood. We detected elevated IL-27 plasma levels in European patients with active visceral disease caused by Leishmania infantum, which returned to basal levels after successful treatment, suggesting this cytokine as a probable infection mediator. We further addressed this hypothesis recurring to two classical susceptible visceral leishmaniasis mouse models. BALB/c, but not C57BL/6 mice, showed increased IL-27 systemic levels after infection, which was associated with an upregulation of IL-27p28 expression by dendritic cells and higher parasite burdens. Neutralization of IL-27 in acutely infected BALB/c led to decreased parasite burdens and a transient increase in IFN-γ+ splenic T cells, while administration of IL-27 to C57BL/6 promoted a local anti-inflammatory cytokine response at the site of infection and increased parasite loads. Overall, we show that, as in humans, BALB/c IL-27 systemic levels are infection dependently upregulated and may favor parasite installation by controlling inflammation.

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“…In the case of cutaneous leishmaniasis (CL), caused by L. major (16), IL-27 signaling is involved in host resistance, since Il-27ra Ϫ/Ϫ mice present increased amounts of parasites. However, during L. amazonensis infection, IL-27 administration leads to higher parasite replication, both in vitro and in vivo (17). In the context of VL caused by L. donovani, Ϫ/Ϫ mice present reduced parasite burdens in the spleen and liver (18).…”

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confidence: 99%

Interleukin-27 (IL-27) Mediates Susceptibility to Visceral Leishmaniasis by Suppressing the IL-17–Neutrophil Response

et al. 2016

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bThe 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-␥ 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. Visceral leishmaniasis (VL), or kala-azar, is a systemic chronic disease with high mortality rates if not treated. It is caused by the parasites Leishmania infantum and L. donovani, and it is estimated that 300,000 new cases and 20,000 deaths occur annually (http://www.who.int/mediacentre/factsheets/fs375/en/). After dermal inoculation by the sandfly vector, the parasite disseminates to the liver, spleen, bone marrow, and lymph nodes of susceptible hosts, causing symptoms such as hepatosplenomegaly, lymphadenopathy, anemia, constant fever, and immunosuppression (1). Even though it is considered one of the six most important parasitic diseases affecting humans, the immunobiology of VL is not completely understood and novel therapeutic approaches are desired.The immune response against Leishmania spp. is critically mediated by gamma interferon (IFN-␥)-producing Th1 cells, which activate macrophages to produce leishmanicidal compounds, such as nitric oxide (NO) (2). Together with IFN-␥, the inflammatory cytokine interleukin-17A (IL-17A) also mediates protection against L. infantum (3, 4). On the other hand, Th2 cytokines are involved in susceptibility to leishmaniasis (2, 5). Moreover, the regulatory cytokines IL-10, IL-21, and IL-27 are produced in the bone marrow of VL patients, suggesting their association with the disease (6).The cytokine IL-27 is a dimer composed of p28...

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IL-27 enhances Leishmania amazonensis infection via ds-RNA dependent kinase (PKR) and IL-10 signaling

Cited by 17 publications

References 40 publications

Visceral Leishmaniasis Patients Display Altered Composition and Maturity of Neutrophils as well as Impaired Neutrophil Effector Functions

Visceral Leishmaniasis Patients Display Altered Composition and Maturity of Neutrophils as well as Impaired Neutrophil Effector Functions

Interleukin-27 Early Impacts Leishmania infantum Infection in Mice and Correlates with Active Visceral Disease in Humans

Interleukin-27 (IL-27) Mediates Susceptibility to Visceral Leishmaniasis by Suppressing the IL-17–Neutrophil Response

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