Macrophage Dectin-1 Expression Is Controlled by Leukotriene B4 via a GM-CSF/PU.1 Axis

Abstract

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 B4 (LTB4). The influence of G protein-coupled receptor ligands such as LTB4 on fungal pattern recognition receptor expression is unknown. In this study, we investigated the role of LTB4 signaling in dectin-1 expression and responsiveness in macrophages. Genetic and pharmacologic approaches showed that LTB4 production and signaling through its high-affinity G protein-coupled receptor leukotriene B4 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. LTB4 increased the expression of the transcription factor responsible for dectin-1 expression, PU.1, and PU.1 small interfering RNA abolished LTB4-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, LTB4 effects on dectin-1, PU.1, and cytokine production were blunted in GM-CSF−/− macrophages. Our results identify LTB4-BLT1 signaling as an unrecognized controller of dectin-1 transcription via GM-CSF and PU.1 that is required for fungi-protective host responses.

Prostaglandin E2Reduces Toll-Like Receptor 4 Expression in Alveolar Macrophages by Inhibition of Translation

“…Because the actions of PGE 2 were our primary focus in this report, the precise mechanisms by which LTB 4 up-regulates tlr4 mRNA remain to be explored. However, because LTB 4 has been shown to increase expression of PU.1 (27), the major transcription factor for tlr4 (28), we speculate that it may in this way increase transcription of tlr4.…”

Too much of a good thing: How modulating LTB 4 actions restore host defense in homeostasis or disease

“…After this, Dr. Peters-Golden’s group pioneered in demonstrating the role of endogenous LTs in amplifying phagocytosis of antibody-opsonized targets [39, 40]. Both genetic and pharmacologic blockage of LTB 4 /BLT1 actions greatly reduces ingestion of a myriad of pathogens, including both gram-positive bacteria ( Streptococcus pneumoniae ) [27], gram-negative bacteria ( Klebsiella pneumoniae [41]), fungi ( Histoplasma capsulatum [42, 43], Candida albicans [44], and Paracoccidioides braziliensis [45]), and parasites ( Leishmania braziliensis [46], L. amazonensis [47], and T. cruzi [38, 48]).…”

Canonical and Noncanonical G-Protein Signaling Helps Coordinate Actin Dynamics To Promote Macrophage Phagocytosis of Zymosan

“…These include phosphatidylinositol 3-kinase and, as mentioned previously, small GTPases, which help coordinate the actin cytoskeleton rearrangements necessary for membrane extensions and particle engulfment. While G-proteins are not known to regulate dectin-1 signaling, their expression levels are partially controlled by signaling through the GPCRs, such as leukotriene B4 receptor 1 (10).…”