Macrophage dectin-1 expression is controlled by leukotriene B4 via a GM-CSF/PU.1 axis.
Pattern recognition receptors for fungi include dectin-1 and mannose receptor, and these mediate phagocytosis, as well as production of cytokines, reactive oxygen species, and the lipid mediator leukotriene B(4) (LTB(4)). The influence of G protein-coupled receptor ligands such as LTB(4) on fungal pattern recognition receptor expression is unknown. In this study, we investigated the role of LTB(4) signaling in dectin-1 expression and responsiveness in macrophages. Genetic and pharmacologic approaches showed that LTB(4) production and signaling through its high-affinity G protein-coupled receptor leukotriene B(4) receptor 1 (BLT1) direct dectin-1-dependent binding, ingestion, and cytokine production both in vitro and in vivo. Impaired responses to fungal glucans correlated with lower dectin-1 expression in macrophages from leukotriene (LT)- and BLT1-deficent mice than their wild-type counterparts. LTB(4) increased the expression of the transcription factor responsible for dectin-1 expression, PU.1, and PU.1 small interfering RNA abolished LTB(4)-enhanced dectin-1 expression. GM-CSF controls PU.1 expression, and this cytokine was decreased in LT-deficient macrophages. Addition of GM-CSF to LT-deficient cells restored expression of dectin-1 and PU.1, as well as dectin-1 responsiveness. In addition, LTB(4) effects on dectin-1, PU.1, and cytokine production were blunted in GM-CSF(-/-) macrophages. Our results identify LTB(4)-BLT1 signaling as an unrecognized controller of dectin-1 transcription via GM-CSF and PU.1 that is required for fungi-protective host responses.
Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA.
C Henrique
CH
Serezani
Steve
S
Kane
Latima
L
Collins
Mariana
M
Morato-Marques
John J
JJ
Osterholzer
Marc
M
Peters-Golden
D000818:Animals; D002176:Candida albicans / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D037181:Lectins, C-Type / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000382:microbiology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000502:physiology*; D018102:Receptors, Leukotriene B4 / Q000172:deficiency / Q000502:physiology; D015534:Trans-Activators / Q000096:biosynthesis / Q000502:physiology*; D014158:Transcription, Genetic / Q000276:immunology; D000099232:Proto-Oncogene Protein Spi-1; D000099181:Dectin-1
D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D037181:Lectins, C-Type; D007975:Leukotriene B4; D011518:Proto-Oncogene Proteins; D018102:Receptors, Leukotriene B4; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; D000099181:Dectin-1