title: Cellular and molecular mechanisms of fungal β-(1→6)-glucan in macrophages.
abstract: Over the last 40 yr, the majority of research on glucans has focused on β-(1→3)-glucans. Recent studies indicate that β-(1→6)-glucans may be even more potent immune modulators than β-(1→3)-glucans. Mechanisms by which β-(1→6)-glucans are recognized and modulate immunity are unknown. In this study, we examined the interaction of purified water-soluble β-(1→6)-glucans with macrophage cell lines and primary peritoneal macrophages and the cellular and molecular consequences of this interaction. Our results indicate the existence of a specific β-(1→6)-glucan receptor that internalizes the glucan ligand via a clathrin-dependent mechanism. We show that the known β-(1→3)-glucans receptors are not responsible for β-(1→6)-glucan recognition and interaction. The receptor-ligand uptake/interaction has an apparent dissociation constant (KD) of ∼ 4 µM, and was associated with phosphorylation of ERK and JNK but not IκB-α or p38. Our results indicate that macrophage interaction with β-(1→6)-glucans may lead to modulation of genes associated with anti-fungal immunity and recruitment/activation of neutrophils. In summary, we show that macrophages specifically bind and internalize β-(1→6)-glucans followed by activation of intracellular signaling and modulation of anti-fungal immune response-related gene regulation. Thus, we conclude that the interaction between innate immunity and β-(1→6)-glucans may play an important role in shaping the anti-fungal immune response.
authors.affiliation: Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Noss
authors.affiliation: Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA Center for Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, TN, USA.
authors.forename: Tammy R
authors.initials: TR
authors.lastname: Ozment
authors.affiliation: Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA Center for Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, TN, USA.
authors.forename: Bridget M
authors.initials: BM
authors.lastname: Graves
authors.affiliation: Center for Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, TN, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Kruppa
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Rice
authors.affiliation: Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA Center for Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, TN, USA williamd@etsu.edu.
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
mesh_terms: D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000382:microbiology / Q000502:physiology*; D008290:Malassezia / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018375:Neutrophil Activation; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000276:immunology*; D047071:beta-Glucans / Q000378:metabolism*
chemical_list: D051192:Receptors, Pattern Recognition; D047071:beta-Glucans
keywords: Fungi; glucan; innate immunity; macrophages; receptor