The C-type Lectin Receptors Dectin-1, MR, and SIGNR3 Contribute Both Positively and Negatively to the Macrophage Response to Leishmania infantum

摘要

Macrophages act as the primary effector cells during Leishmania infection through production of reactive oxygen species (ROS) and interleukin-1β (IL-1β). However, how macrophage-killing mechanisms are activated during Leishmania-macrophage interactions is poorly understood. Here, we report that the macrophage response against Leishmania infantum invivo is characterized by an M2b-like phenotype and C-type lectin receptors (CLRs) signature composed of Dectin-1, mannose receptor (MR), and the DC-SIGN homolog SIGNR3 expression. Dectin-1 and MR were crucial for the microbicidal response as indicated by the fact that they activated Syk-p47phox and arachidonic acid (AA)-NADPH oxidase signaling pathways, respectively, needed for ROS production and also triggered Syk-coupled signaling for caspase-1-induced IL-1β secretion. In contrast, SIGNR3 has divergent functions during Leishmania infantum pathogenesis; this CLR favored parasite resilience through inhibition of the LTB4-IL-1β axis. These pathways also operated during infection of primary human macrophages. Therefore, our study promotes CLRs as potential targets for treatment, diagnosis, and prevention of visceral leishmaniasis. ?M2b-like macrophages express Dectin-1, MR, and SIGNR3 upon Leishmania challenge?Dectin-1 and MR favor the host response whereas SIGNR3 boosts Leishmania's resilience?Dectin-1 and MR trigger Syk-p47phox and AA-NADPH oxidase for ROS release?Caspase-1-induced IL-1β is activated by Dectin-1 and MR or inhibited by SIGNR3.