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 <i>Leishmania infantum</i> 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 <i>Leishmania</i> 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 <i>L. infantum</i> 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 <i>nitric oxide synthase</i> (iNOS) expression in neutrophils but not in macrophages. <i>In vitro</i>, infected TLR2^-/- neutrophils presented deficient iNOS expression, nitric oxide (NO) and TNF-α production, decreased expression of CD11b and reduced <i>L. infantum</i> 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 <i>L. infantum</i> infection.