Immunomodulation of Fungal β-Glucan in Host Defense Signaling by Dectin-1

Abstract

During the course of evolution, animals encountered the harmful effects of fungi, which are strong pathogens. Therefore, they have developed powerful mechanisms to protect themselves against these fungal invaders. β-Glucans are glucose polymers of a linear β(1,3)-glucan backbone with β(1,6)-linked side chains. The immunostimulatory and antitumor activities of β-glucans have been reported; however, their mechanisms have only begun to be elucidated. Fungal and particulate β-glucans, despite their large size, can be taken up by the M cells of Peyer's patches, and interact with macrophages or dendritic cells (DCs) and activate systemic immune responses to overcome the fungal infection. The sampled β-glucans function as pathogen-associated molecular patterns (PAMPs) and are recognized by pattern recognition receptors (PRRs) on innate immune cells. Dectin-1 receptor systems have been incorporated as the PRRs of β-glucans in the innate immune cells of higher animal systems, which function on the front line against fungal infection, and have been exploited in cancer treatments to enhance systemic immune function. Dectin-1 on macrophages and DCs performs dual functions: internalization of β-glucan-containing particles and transmittance of its signals into the nucleus. This review will depict in detail how the physicochemical nature of β-glucan contributes to its immunostimulating effect in hosts and the potential uses of β-glucan by elucidating the dectin-1 signal transduction pathway. The elucidation of β-glucan and its signaling pathway will undoubtedly open a new research area on its potential therapeutic applications, including as immunostimulants for antifungal and anti-cancer regimens.

Keywords: Dectin-1; Peyer's patch; Signal transduction; Toll-like receptor (TLR); Triple helix; β-Glucan.

Fig. 1.. Uptake of β-glucan in the small intestine and activation of innate and adaptive immune cells of Peyer's patches, lymph nodes, and systemic organs. Orally administered β-glucans can be either absorbed through M cells or through binding to the projected tips of dendritic cells (DCs) in the follicle-associated epithelium (FAE) of Peyer's patches, and subsequently bind to dectin-1 and TLR2. The macrophages or DCs engulf β-glucans and fragmented β-glucans (FBGs) are secreted in the lymph nodes. FBGs, like soluble β-glucans, bind to dectin-1, but are unable to activate macrophages and DCs. However, FGBs can activate NK cells and granulocytes by binding to complement receptor 3 (CR3) on these cells. The NK cells and cytokine-stimulated cytotoxic T lymphocytes (CTLs) secrete perforins and granzymes, which make pores and fragmenting the DNA in tumor cells, respectively. The FBG-bound granulocytes together with activated neutrophils and macrophages then remove the infecting fungi.

Fig. 2.. Recognition of particulate and soluble β-glucans by dectin-1 and signal transduction in macrophages and DCs. When particulate β-glucan binds, dectin-1 molecules cluster, which excludes CD45 and CD148 and enables Src to associate and phosphorylate the hemITAM motif of dectin-1. Syk then binds to the phosphorylated hemITAM domain. In contrast, when dectin-1 is empty or is bound to small soluble β-glucan, it cannot exclude the CD45 and CD148 phosphatases, which remove the phosphate from the hemITAM domain. Therefore, no signal or only a weak signal is generated. Syk-mediated phagocytosis occurs instantly while the so-called integrated transcriptional response (ITR) begins with PLCγ activation. Three major pathways exist in the ITR: 1) CBM complex modulates the signaling for NF-κB via NEMO complex and, in parallel, activates MAPK to activate AP-1 expression after PKCδ activation; 2) Syk also triggers PLCγ, and subsequently calcineurin, which eventually turns on NFAT; 3) following Syk-dependent ROS production by NADPH oxidase, NLRP3 initiates IL-1 processing. In addition to ITR, β-glucans trigger the TLR2/6 dimeric receptor to attract MyD88 protein, which activates a series of kinases to activate on the NEMO/IKK complex, which finally induces NF-κB, which is also activated independent of Syk. In this Syk-independent pathway, Raf-1 induces p60 and this nuclear factor subsequently induces NF-κB. BCL-10: B cell lymphoma 10, CARD9: Caspase-recruitment domain 9, CRD: Carbohydrate recognition domain, IRAK: IL-1 receptor-associated kinase, MALT1: Mucosa-associated lymphoid tissue lymphoma translocation protein 1, MAPK: Mitogen-activated protein kinase, NEMO: NF-κB essential modulator, NLRP3: Nucleotide-binding domain and leucine-rich repeat containing protein 3, TAK: TGF-β-activated kinase, TLR: Toll-like receptor, TRAF: TNF receptor associated factor.