Cellular and molecular mechanisms of fungal ß-(1→6)-glucan in macrophages.

Over the last 40 yr, the majority of research on glucans has focused on ß-(1→3)-glucans. Recent studies indicate that ß-(1→6)-glucans may be even more potent immune modulators than ß-(1→3)-glucans. Mechanisms by which ß-(1→6)-glucans are recognized and modulate immunity are unknown. In this study, we examined the interaction of purified water-soluble ß-(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 ß-(1→6)-glucan receptor that internalizes the glucan ligand via a clathrin-dependent mechanism. We show that the known ß-(1→3)-glucans receptors are not responsible for ß-(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 ß-(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 ß-(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 ß-(1→6)-glucans may play an important role in shaping the anti-fungal immune response.