The Equivocal Role of Th17 Cells and Neutrophils on Immunopathogenesis of Leishmaniasis

Abstract

Advances in the understanding of leishmaniasis progression indicate that cellular interactions more complex than the Th1/Th2 paradigm define the course of infection. Th17 cells are a crucial modulator of adaptive immunity against Leishmania parasites acting mainly on neutrophil recruitment and playing a dual role at the site of infection. This review describes the roles of both these cell types in linking innate defense responses to the establishment of specific immunity. We focus on the Th17–neutrophil interaction as a crucial component of anti-Leishmania immunity, and the clinical evolution of cutaneous or visceral leishmaniasis. To date, information obtained through experimental models and patient evaluations suggests that the influence of the presence of interleukin (IL)-17 (the main cytokine produced by Th17 cells) and neutrophils during Leishmania infections is strictly dependent on the tissue (skin or liver/spleen) and parasite species. Also, the time at which neutrophils are recruited, and the persistence of IL-17 in the infection microenvironment, may also be significant. A clearer understanding of these interactions will enable better measurement of the influence of IL-17 and its regulators, and contribute to the identification of disease/resistance biomarkers.

Transcriptional Blood Signatures for Active and Amphotericin B Treated Visceral Leishmaniasis in India

“…IL-17 is a potent activator of neutrophils, both through lineage expansion and through their recruitment by regulating chemokine expression. While IL-17 perturbation was not identified in our whole blood transcriptional profiles associated with human VL, evidence from murine models [51] demonstrate a strong role for IL-17 and neutrophils in parasite clearance from liver and spleen. Duthie and coworkers [50] have shown that both IL-10 and IL-17 cytokines are elevated in the serum of active VL patients, reverting to baseline levels with standard antimonial treatments.…”

Protective or Detrimental? Understanding the Role of Host Immunity in Leishmaniasis

“…Once inoculated into the host dermis by an infected sandfly, infective metacyclic promastigotes of Leishmania are engulfed by a variety of immune cells, such as resident dermal dendritic cells, macrophages and infiltrating neutrophils that act as the first line of defense [20][21][22][23][24]. The rapid and massive recruitment of neutrophils to the site of parasite inoculation has been well documented and associated with the enhancement of the disease [20][21][22]. Neutrophil-driven inflammation seems to be mostly triggered by the insertion of the sandfly's proboscis into the skin, provoking tissue damage [24,25].…”

“…Meantime, an anti-inflammatory phenotype is correlated with a predominant Th2 response characterized by the production of IL-4, IL-13, IL-10, and Transforming Growth Factor (TGF)-β cytokines; enhanced arginase activity; polyamine biosynthesis; and IL-21-mediated down-regulation of iNOS, TNF-α, and Toll-like receptor (TLR)-4, favoring intracellular proliferation of Leishmania parasites and disease progression [56,57] (Figure 2). Additionally, the role of other T cell subtypes in Leishmania pathogenesis, such as T regulatory cells (Treg), CD8+ T cytotoxic, and Th17 effector cells, is coming to light [20,58,59]. Th17 cells are suggested to participate in the balance of inflammatory cytokines, modulating adaptive immunity, and also secret the IL-17 cytokine that contributes to neutrophil recruitment [20].…”

“…Additionally, the role of other T cell subtypes in Leishmania pathogenesis, such as T regulatory cells (Treg), CD8+ T cytotoxic, and Th17 effector cells, is coming to light [20,58,59]. Th17 cells are suggested to participate in the balance of inflammatory cytokines, modulating adaptive immunity, and also secret the IL-17 cytokine that contributes to neutrophil recruitment [20]. On the other hand, Th2 differentiation leads to production of anti-inflammatory cytokines, which downregulate iNOS activity and stimulates arginase, culminating in parasite survival and proliferation.…”

“…Moreover, IL-17, an inflammatory cytokine involved in neutrophil recruitment, is particularly upregulated in MCL patients [102]. The production of IL-17, which is mostly mediated by Th17 cells, is induced by IL-23 and IL-1β [20]. In turn, IL-1β apparently promotes disease progression in C57BL/6 mice by mediating the expansion of Th17 cells [60].…”