The Response of Human Macrophages to β-Glucans Depends on the Inflammatory Milieu

Abstract

Backgroundβ-glucans are fungal cell wall components that bind to the C-type lectin-like receptor dectin-1. Polymorphisms of dectin-1 gene are associated with susceptibility to invasive fungal infection and medically refractory ulcerative colitis. The purpose of this study has been addressing the response of human macrophages to β-glucans under different conditions mimicking the composition of the inflammatory milieu in view of the wide plasticity and large range of phenotypical changes showed by these cells, and the relevant role of dectin-1 in several pathophysiological conditions.Principal FindingsSerum-differentiated macrophages stimulated with β-glucans showed a low production of TNFα and IL-1β, a high production of IL-6 and IL-23, and a delayed induction of cyclooxygenase-2 and PGE2 biosynthesis that resembled the responses elicited by crystals and those produced when phagosomal degradation of the phagocytic cargo increases ligand access to intracellular pattern recognition receptors. Priming with a low concentration of LPS produced a rapid induction of cyclooxygenase-2 and a synergistic release of PGE2. When the differentiation of the macrophages was carried out in the presence of M-CSF, an increased expression of dectin-1 B isoform was observed. In addition, this treatment made the cells capable to release arachidonic acid in response to β-glucan.ConclusionsThese results indicate that the macrophage response to fungal β-glucans is strongly influenced by cytokines and microbial-derived factors that are usual components of the inflammatory milieu. These responses can be sorted into three main patterns i) an elementary response dependent on phagosomal processing of pathogen-associated molecular patterns and/or receptor-independent, direct membrane binding linked to the immunoreceptor tyrosine-based activation motif-bearing transmembrane adaptor DNAX-activating protein 12, ii) a response primed by TLR4-dependent signals, and iii) a response dependent on M-CSF and dectin-1 B isoform expression that mainly signals through the dectin-1 B/spleen tyrosine kinase/cytosolic phospholipase A2 route.

Polarization of the Innate Immune Response by Prostaglandin E2: A Puzzle of Receptors and Signals

“…Macrophages cultured in the presence of human serum show a high sensitivity to LPS as judged from a rapid induction of COX-2 and a high production of PGE 2 . In contrast, particulate zymosan, an extract of the Saccharomyces cerevisiae cell wall mainly composed of b-glucans, only induces COX-2 expression several hours after particle uptake (Municio et al, 2013). This putative phagolysosomal route of PGE 2 production is synergistically enhanced by low concentrations of LPS, which agrees with the results observed with crystal-like materials (Kuroda et al, 2011).…”

“…Attempts to correlate the state of macrophage differentiation with eicosanoid release have steadily shown a predominant production of PGE 2 and PGD 2 and a varying pattern of response dependent on the presence of costimulatory substances. For instance, growth factors such as macrophase colony-stimulating factor and granulocyte macrophage colony-stimulating factor elicit profound changes on the expression of receptors such as DC-SIGN and the dectin-1 B isoform, that is, the isoform displaying the most efficient productive binding to b-glucans (Rosas et al, 2008;Municio et al, 2013). Macrophages cultured in the presence of human serum show a high sensitivity to LPS as judged from a rapid induction of COX-2 and a high production of PGE 2 .…”

The Synergy of Endotoxin and (1→3)-β-D-Glucan, from Gut Translocation, Worsens Sepsis Severity in a Lupus Model of Fc Gamma Receptor IIb-Deficient Mice

“…This supports the endotoxin-BG synergy observed in several previous studies [19,28]. However, BG alone could not induce macrophage cytokine production in either FcGRIIb-/-or wild-type mice, sug- gesting a limited independent proinflammatory potential [29,30]. The main pattern recognition receptors responsible for the detection of endotoxin and BG are TLR-4 and dectin-1, respectively [31].…”

Neither Dectin-2 nor the Mannose Receptor Is Required for Resistance to Coccidioides immitis in Mice

“…We do not know why the two cell types had different requirements for Dectin-2, but others have shown that mouse bone marrow-derived macrophages and BMDC react differently to Dectin-1 agonists because macrophages and BCs are reprogrammed by cytokines used as in vitro growth factors (75). Municio et al recently showed that human macrophages and DCs responded differently to zymosan and ␤-glucan depending on whether or not M-CSF was used to mature the cells or if TLR ligands or IFN-␥ were added to the reaction mixture (76). In our in vitro assays with BMDC, we did not detect IL-12p70 or IFN-␥, perhaps because we were studying genetically susceptible B6 mice, which do not generate Th1 immune responses to this infection (20,77).…”

“…In vivo spherules have an outer membrane made up of membranous glycoprotein (SOWgp) (87) that can be lost during in vitro cultivation, and SOWgp could interact with other receptors or prevent recognition by CLR of mannose ligands in the cell wall. In addition, we used FKS that were too large to be ingested and so probably did not interact with intracellular TLRs that influence the way macrophages and DCs respond to zymosan (76). Since a decrease in cytokine production by Dectin-1 Ϫ/Ϫ macrophages and BMDC in vivo does predict greater susceptibility to infection (23), we can only conclude that in vitro results may not predict susceptibility, which needs to be determined in vivo.…”