Research Progress on the Mechanisms of Immunomodulatory Effects of Plant Polysaccharides (Part Ⅱ)

Impact on Dendritic Cells

Dendritic cells (DCs) are widely recognized as the most potent antigen-presenting cells (APCs) that bridge innate and adaptive immunity. They are capable of phagocytosing, processing, and presenting antigens, thereby activating cytotoxic T cells, natural killer (NK) cells, macrophages, and B cells. Astragalus polysaccharide (PG2), an active component extracted from the dried roots of Astragalus membranaceus, has been shown to promote the functional maturation of DCs, ultimately enhancing T-cell-mediated anti-cancer immunity.

Moreover, polysaccharides extracted from the Chinese fringe tree pods (CFP) can upregulate the expression of CD80, CD83, and CD86, as well as MHC class I and II molecules in monocyte-derived dendritic cells (MDDCs). This stimulation induces the production of pro-inflammatory cytokines in MDDCs. CFP also directly activates distinct subsets of human peripheral blood dendritic cells (PBDCs), namely BDCA1+ and BDCA3+ subpopulations. Stimulated BDCA1+ PBDCs further promote the activation and proliferation of autologous CD4+ T cells, while BDCA3+ PBDCs activate autologous CD8+ T cells, leading to the production of cytotoxic mediators that modulate the immune function of the body.

Impact on Cytokines

Cytokines are a class of small-molecule glycoproteins synthesized and secreted by immune cells and certain stromal cells in response to stimulation. They play a crucial role in regulating immune and inflammatory responses. Based on their distinct mechanisms of action, cytokines are classified into various categories such as interleukins (ILs), interferons (IFNs), tumor necrosis factors (TNFs), and growth factors. These cytokines primarily function by binding to their respective receptors, thereby modulating cell growth, differentiation, and regulating immune responses.

Research Findings

Studies have demonstrated that the encapsulation of atractylodes macrocephala polysaccharide (AMP) within mesoporous silica nanoparticles addresses the issue of rapid metabolism when AMP is directly administered in vivo. This approach not only enhances the proliferation and phagocytic capabilities of phagocytic cells but also stimulates the production of cytokines such as TNF-α, IL-6, IL-12, and IL-1β.

Lycium barbarum polysaccharide (LBP) promotes the expression of activation molecules like CD86 and MHC-II on macrophages, stimulating their secretion of nitric oxide (NO), IL-6, and TNF-α, thereby increasing their phagocytic activity. Korean red ginseng polysaccharide (KRG-P) induces the production of NO, IL-6, and TNF-α in RAW264.7 cells, upregulating the expression of nitric oxide synthase 2 (NOS2), IL-6, and TNF-α in a dose-dependent manner, and enhancing MAPK phosphorylation.

Mulberry leaf polysaccharide (MLP) possesses various biological properties. In cyclophosphamide-induced immunosuppressed (CTX) mice, MLP treatment improved thymus and spleen indices, repaired damaged intestinal barriers, and modulated inflammatory cytokine levels. It also alleviated oxidative damage to the liver. Additionally, in CTX-treated mice, MLP was associated with higher levels of Bacteroidetes, lower levels of Firmicutes, Clostridium butyricum, and Eubacterium, and restored acetate, propionate, and butyrate levels reduced by CTX. These findings suggest that MLP, as a unique component, may regulate immune responses by altering gut microbiota spatial structures and short-chain fatty acid (SCFA) profiles.

When administered to mouse intestinal tissues, Jinqianlian polysaccharide significantly increased the secretion levels of TNF-α and IL-10 cytokines. Ginseng root polysaccharide (RGRP) activates macrophages, enhancing NO secretion and phagocytic capacity while upregulating IL-6, IL-12, and TNF-α expression. In vitro intervention with Sterculia foetida polysaccharide (SFPSA) on mouse splenic lymphocytes significantly elevated IFN-γ, NO, and IL-6 cytokine secretion levels, revealing a biphasic immune modulation effect: immunostimulatory at low levels and immunosuppressive at high levels.

Polygonatum odoratum polysaccharide activates macrophages via type III complement receptor (CR3) mediation, increasing the secretion of NO, IL-1β, IL-6, and IL-10, thereby enhancing immune regulation. Neutral ginger polysaccharide (NGP) isolated from ginger significantly enhances macrophage proliferation without cytotoxicity, boosting the production of immune mediators (NO, TNF-α, IL-1β, and IL-6), indicating its potential as an immunomodulatory agent.

Regulation of Immune Signaling in the Body

1. Influence on cAMP and cGMP Signaling Systems

Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are crucial second messengers within cells. Elevated levels of cAMP and cGMP participate in cell activation processes, including the promotion of lymphocyte differentiation.

Astragalus Polysaccharide (APS) Effect: When the concentration of APS reaches 200 μg/mL, it has a pronounced effect on reducing cAMP levels in mouse splenic lymphocytes while significantly stimulating cGMP production in the body. This indicates APS's regulatory role in balancing these important second messengers.

Allium Mongolicum Polysaccharide (AMP) Effect: AMP promotes a rapid and dose-dependent increase in both cAMP and cGMP concentrations in sheep peripheral blood lymphocytes. This enhancement is mediated by the activation of adenylyl cyclase under the influence of adenosine triphosphate (ATP), ultimately leading to an elevation in cAMP levels. This suggests that AMP can modulate immune responses by modulating intracellular signaling cascades involving cAMP and cGMP.

2. Impact on Ca²⁺ Conduction

Ca²⁺ serves as a vital second messenger in the inositol phospholipid metabolic pathway, not only responsible for cellular signal transduction but also playing a crucial role in lymphocyte signaling and functional realization. Studies have shown that polysaccharides such as aloe vera polysaccharide, astragalus polysaccharide, and achyranthes polysaccharide can all influence inositol phosphate metabolism, leading to the activation of phospholipases and the hydrolysis of phosphatidylinositol bisphosphate (PIP2). This process results in an increase in the concentrations of inositol trisphosphate (IP3) and diacylglycerol (DAG), which promotes the influx of extracellular calcium and the release of intracellular calcium, thereby elevating the intracellular Ca²⁺ concentration. This elevation in Ca²⁺ concentration is crucial for various cellular processes, including immune cell activation and function.

3. Impact on Nitric Oxide (NO)

Nitric oxide (NO), as a cytotoxic effector molecule, directly acts on macrophages to inhibit and kill viruses, cancer cells, and other pathogens, thereby enhancing immune responses. Polysaccharides induce the release of cytokines (IL-1β, IL-2) and tumor necrosis factor (TNF), which individually or collectively stimulate RAW264.7 macrophages to activate and release cellular immune mediators such as NO. This further activates other immune cells like T cells and natural killer cells, ultimately enhancing the body's immune defense function.

Moreover, plant polysaccharides have demonstrated additional immunomodulatory effects. For instance, Glycyrrhizae Radix Polysaccharides GiP-B1 and GiP, when cultured for 48 hours, significantly increased the expression of surface marker molecules on mouse bone marrow-derived dendritic cells (DCs), promoting DC maturation. Studies investigating the effect of different doses of Cyclocarya paliurus polysaccharide on enhancing anti-red blood cell (RBC) antibody levels in mice found that as polysaccharide concentrations increased, there was a corresponding increase in RBC content in mouse serum. Additionally, using a cell hemolysis method to study the anti-complement activity of Jinchangzao polysaccharide fractions JCS-1, JCS-2, and sulfated modified polysaccharides Sul-JCS-14, Sul-JCS-24, it was shown that Sul-JCS-14 and Sul-JCS-24 strongly inhibited both the classical and alternative complement pathways.

Plant polysaccharides, with their abundant sources and low cost, have garnered increasing attention from scientific researchers in recent years. Studies conducted at various levels, from organ to cellular and molecular, have consistently revealed the immunomodulatory effects of polysaccharides. These include promoting the proliferation of immune cells, enhancing both specific and non-specific immune functions, and increasing the secretion of cytokines. Furthermore, due to their minimal adverse effects, plant polysaccharides hold great potential as immune modulators.

To date, numerous polysaccharide-based drugs have been introduced into clinical practice, and some have already obtained national approval for market entry. Their primary clinical applications are in immune regulation and anti-tumor therapy. Examples of such polysaccharides include astragalus polysaccharide, shiitake polysaccharide, ganoderma polysaccharide, poria cocos polysaccharide, and ginseng polysaccharide.

Reference Sources:

[1] Lin Zhimin, Xiao Jian. Research Progress on the Immunomodulatory Effects of Plant Polysaccharides [J]. Labeled Immunoassays and Clinical Medicine, 2022, 29(07): 1252-1255.

[2] Yang Xuhua, Zhao Mengxiao, Chen Hong, et al. Research Progress on the Mechanisms of Immunomodulatory Effects of Plant Polysaccharides [J]. Journal of Food Safety and Quality, 2021, 12(13): 5349-5355.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.

Related Reading: Research Progress on the Mechanisms of Immunomodulatory Effects of Plant Polysaccharides (Part I)