Toll-Like Receptor 2 Is Required for Inflammatory Process Development during Leishmania infantum Infection

Abstract

Visceral leishmaniasis (VL) is a chronic and fatal disease caused by Leishmania infantum in Brazil. Leukocyte recruitment to infected tissue is a crucial event for the control of infections such as VL. Among inflammatory cells, neutrophils are recruited to the site of Leishmania infection, and these cells may control parasite replication through oxidative or non-oxidative mechanisms. The recruitment, activation and functions of the neutrophils are coordinated by pro-inflammatory cytokines and chemokines during recognition of the parasite by pattern recognition receptors (PRRs). Here, we demonstrated that the Toll-like receptor 2 (TLR2) signaling pathway contributes to the development of the innate immune response during L. infantum infection. The protective mechanism is related to the appropriate recruitment of neutrophils to the inflammatory site. Neutrophil migration is coordinated by DCs that produce CXCL1 and provide a prototypal Th1 and Th17 environment when activated via TLR2. Furthermore, infected TLR2−/− mice failed to induce nitric oxide synthase (iNOS) expression in neutrophils but not in macrophages. In vitro, infected TLR2−/− neutrophils presented deficient iNOS expression, nitric oxide (NO) and TNF-α production, decreased expression of CD11b and reduced L. infantum uptake capacity. The non-responsive state of neutrophils is associated with increased amounts of IL-10. Taken together, these data clarify new mechanisms by which TLR2 functions in promoting the development of the adaptive immune response and effector mechanisms of neutrophils during L. infantum infection.

TLR2 Signaling in Skin Nonhematopoietic Cells Induces Early Neutrophil Recruitment in Response to Leishmania major Infection

“…Neutrophils play important roles not only in the cutaneous forms but also in the experimental visceral form of the disease (Dey et al, 2018, McFarlane et al, 2008, Sacramento et al, 2015, Smelt et al, 2000. Decreased neutrophil recruitment in the liver and spleen of L. infantuminfected Tlr2 -/mice was recently described (Sacramento et al, 2017) further implying the importance of TLR2 signalling in the inflammatory response to infection with Leishmania spp inducing visceral diseases. Leishmania exposure to human primary keratinocytes induced cytokine and chemokine production in vitro, however, L. infantum was a better inducer than L.…”

Leishmania species‐dependent functional duality of toll‐like receptor 2

“…This attenuated neutrophil activity was associated with high IL‐10 expression. Indeed, the neutrophils from TLR2‐deficient mice produce higher amounts of IL‐10 which inhibits iNOS, but induces Arginase‐1 expression, resulting in arginine depletion and reduced iNOS activity . These observations clearly indicate that TLR2 performs a fundamental role in heightening of the protective adaptive immune response and anti‐parasitic functions of the neutrophils during L. infantum infection (Figure ).…”

Leishmania donovani Induces Autophagy in Human Blood–Derived Neutrophils

“…3E). Prior knowledge shows binding of LPG to TLR2 on host macrophages (37,38) and NK cells (39) and also engagement of the TLR2 and four receptors by LPG on mouse neutrophils to trigger the innate immune responses (40). Blocking of TLR2 and 4 signaling with TIRAPinh, a cellpermeable MyD88-specific inhibitory peptide (41) (Fig.…”