Toll-Like Receptors in Leishmania Infections: Guardians or Promoters?

Figure 1

Model for the activation of TLR2 by Leishmania sp., leading to a proinflammatory (left), or anti-inflammatory arm (centre and right). In early studies, L. major stimulated the transcription of IL1α through a MyD88-dependent pathway, but not the IL1α production at the protein level, suggesting the triggering of anti-inflammatory stimuli negatively controlling IL1-α production [22]. LPG or additional undefined TLR2 ligands promote the synthesis of cytokines, nitric oxide (NO), and reactive oxygen species (ROS) that are related to parasite killing and to the development of a protective Th1 response, through MyD-88-dependent pathways [22–29]. L. major LPG also induces the production of suppressors of the cytokine signaling family proteins SOCS-1 and SOCS-3 [26], whose activities are associated with diminished cytokine production and prevention of TLR4 signaling [30]. Lack of TLR2 increased the resistance to infections with L. braziliensis [31] and L. amazonensis [32] decreased lesion formation and parasite burdens, suggesting that TLR2 is required for disease promotion. In RAW macrophages, the infection with L. amazonensis promotes the phosphorylation of PKR and the activation of the PKR promoter and enhances the synthesis of both PKR and of type 1-IFNs, and those events require TLR2 [33]. The levels of SOD1 expression are elevated in association with PKR activation and IFNβ production, resulting in increased parasite replication [33]. L. donovani downmodulates TLR2 responses in macrophages by inhibiting MAPp38 kinase, leading to IL10 production [34]. The dashed lines indicate that intermediate steps of the pathways are either not identified or not represented in the figure.