title: The C-type lectin receptors dectin-1, MR, and SIGNR3 contribute both positively and negatively to the macrophage response to Leishmania infantum.
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.
authors.affiliation: Université de Toulouse, UPS, UMR 152 (PHARMA-DEV), Toulouse 31432, France; IRD, UMR 152, Toulouse 31432, France.
authors.forename: Lise
authors.initials: L
authors.lastname: Lefèvre
authors.forename: Geanncarlo
authors.initials: G
authors.lastname: Lugo-Villarino
authors.forename: Etienne
authors.initials: E
authors.lastname: Meunier
authors.forename: Alexis
authors.initials: A
authors.lastname: Valentin
authors.forename: David
authors.initials: D
authors.lastname: Olagnier
authors.forename: Hélène
authors.initials: H
authors.lastname: Authier
authors.forename: Carine
authors.initials: C
authors.lastname: Duval
authors.forename: Christophe
authors.initials: C
authors.lastname: Dardenne
authors.forename: José
authors.initials: J
authors.lastname: Bernad
authors.forename: Jean Loup
authors.initials: JL
authors.lastname: Lemesre
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.forename: Olivier
authors.initials: O
authors.lastname: Neyrolles
authors.forename: Bernard
authors.initials: B
authors.lastname: Pipy
authors.forename: Agnès
authors.initials: A
authors.lastname: Coste
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism*; D018314:Leishmania infantum / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000276:immunology / Q000469:parasitology; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors; D008264:Macrophages / Q000276:immunology*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase; D000099181:Dectin-1
chemical_list: D015703:Antigens, CD; D016718:Arachidonic Acid; D020170:Caspase 1; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D007975:Leukotriene B4; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D019255:NADPH Oxidases; D011505:Protein-Tyrosine Kinases; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D000072377:Syk Kinase; D000099181:Dectin-1; C494354:SIGNR3 protein, mouse; C060505:neutrophil cytosolic factor 1; C000606896:SYK protein, human; C000606897:Syk protein, mouse