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

Abstract

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...

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

“…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). …”

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

“…The role of IL-27 during Leishmania infection has been addressed using animal models by several groups (9, 10, 12, 30). The general conclusion was that IL-27 controls inflammation and pathology through limitation of IFN-γ (12) and IL-17 (9) production by CD4 + T cells, resulting in a permissive environment for the infection.…”

“…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). However, whether the absence of the EBI3 subunit has an impact early after infection was not addressed in this work.…”

Comparison of pro‐inflammatory cytokines of non‐healing and healing cutaneous leishmaniasis

“…Leishmanicidal activity of IFN‐ γ is, however, supported by IL‐17a cytokine produced by TH17 cells. These cells protect mucosal and skin tissue of Leishmania ‐infected mice through neutrophil and monocyte recruitment .…”