The C-type lectin receptors dectin-1, MR, and SIGNR3 contribute both positively and negatively to the macrophage response to Leishmania infantum

Lise Lefèvre; Geanncarlo Lugo-Villarino; Etienne Meunier; Alexis Valentin; David Olagnier; Hélène Authier; Carine Duval; Christophe Dardenne; José Bernad; Jean Loup Lemesre; Johan Auwerx; Olivier Neyrolles; Bernard Pipy; Agnès Coste

doi:10.1016/j.immuni.2013.04.010

The C-type lectin receptors dectin-1, MR, and SIGNR3 contribute both positively and negatively to the macrophage response to Leishmania infantum

Immunity. 2013 May 23;38(5):1038-49. doi: 10.1016/j.immuni.2013.04.010. Epub 2013 May 16.

Authors

Lise Lefèvre¹, Geanncarlo Lugo-Villarino, Etienne Meunier, Alexis Valentin, David Olagnier, Hélène Authier, Carine Duval, Christophe Dardenne, José Bernad, Jean Loup Lemesre, Johan Auwerx, Olivier Neyrolles, Bernard Pipy, Agnès Coste

Affiliation

¹ Université de Toulouse, UPS, UMR 152 (PHARMA-DEV), Toulouse 31432, France; IRD, UMR 152, Toulouse 31432, France.

PMID: 23684988
DOI: 10.1016/j.immuni.2013.04.010

Abstract

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 in vivo 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, CD / metabolism*
Arachidonic Acid / metabolism
Caspase 1 / metabolism
Cells, Cultured
Humans
Interleukin-1beta / antagonists & inhibitors
Interleukin-1beta / metabolism
Intracellular Signaling Peptides and Proteins / metabolism
Lectins, C-Type / immunology
Lectins, C-Type / metabolism*
Leishmania infantum / immunology*
Leishmaniasis, Visceral / immunology
Leishmaniasis, Visceral / parasitology
Leukotriene B4 / antagonists & inhibitors
Macrophages / immunology*
Mannose Receptor
Mannose-Binding Lectins / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
NADPH Oxidases / metabolism
Protein-Tyrosine Kinases / metabolism
RNA Interference
RNA, Small Interfering
Reactive Oxygen Species / metabolism
Receptors, Cell Surface / metabolism*
Signal Transduction
Syk Kinase

Substances

Antigens, CD
Interleukin-1beta
Intracellular Signaling Peptides and Proteins
Lectins, C-Type
Mannose Receptor
Mannose-Binding Lectins
RNA, Small Interfering
Reactive Oxygen Species
Receptors, Cell Surface
SIGNR3 protein, mouse
dectin 1
Leukotriene B4
Arachidonic Acid
NADPH Oxidases
neutrophil cytosolic factor 1
Protein-Tyrosine Kinases
SYK protein, human
Syk Kinase
Syk protein, mouse
Caspase 1