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

Plant polysaccharides, abbreviated as PPS, are compounds composed of many identical or different monosaccharides linked by α- or β-glycosidic bonds. They encompass important biomacromolecules such as starch, cellulose, pectin, and polysaccharides, serving as primary energy sources for life activities in organisms. Research has revealed that plant polysaccharides possess various physiological functions, including antiviral, antibacterial, antitumor, hypoglycemic, hypolipidemic, and antithrombotic effects. Furthermore, recent studies by scholars both domestically and internationally have found that various plant polysaccharides, such as Cordyceps militaris polysaccharide, Astragalus polysaccharide, and ginseng polysaccharide, exhibit significant immunomodulatory activities, enhancing the immune responsiveness of macrophages, lymphocytes, and other immune cells in the body.

As research continues to deepen, the mechanisms of immunomodulatory effects and functional factors of plant polysaccharides are becoming increasingly clear. These mechanisms primarily involve the activation of macrophages and the complement system, promotion of the growth of immune organs, stimulation of the production of related cytokines to activate T and B lymphocytes, modulation of erythrocyte immunity affecting protein synthesis and antibody generation, thereby influencing immune signaling in the body. This includes promoting the production of interleukins and interferons, participating in the regulation of the neuro-endocrine-immune system, enhancing the immune system's recognition of antigens, and improving immune tolerance capabilities in response to immune system damage.

The Impact of Plant Polysaccharides on Innate Immunity

Innate immunity, also known as natural or non-specific immunity, is characterized by its broad spectrum, rapid response, and minimal population variability. It is an immune mechanism that individuals possess from birth and provides protection against non-specific pathogen infections. Innate immunity encompasses immune cells such as macrophages and natural killer cells (NK cells).

1. Impact on Macrophages

Macrophages are white blood cells located within tissues, derived from monocytes. They can function as fixed cells or free-roaming cells to phagocytize and digest pathogens, as well as activate lymphocytes or other immune cells. Macrophages not only initiate innate immune responses but also exhibit resistance to infections and inflammation. When polysaccharides bind to specific membrane receptors on macrophages, the immune response is formally activated, and with increasing doses, it exhibits significant regulatory effects on directly killing pathogens. Plant polysaccharides often enhance the phagocytic activity of macrophages by altering their morphology, promoting the production of nitric oxide (NO), increasing the secretion of cytokines by macrophages, affecting intracellular enzyme activity, and reducing the secretion of macrophage migration inhibitory factor.

Studies have found that a certain concentration of poria cocos polysaccharide can increase the size of macrophages and alter their morphology, thereby enhancing their immune function. Homogeneous laminarin has been shown to reduce the proportion of atherosclerotic lesions in a high-fat diet mouse model, alleviate lipid deposition in macrophages caused by oxidized low-density lipoprotein (Ox-LDL), decrease the expression of M1 macrophage markers, increase the expression of M2 macrophage markers, and thereby lower the M1/M2 macrophage phenotype ratio, affecting the phagocytic function of these cells. A novel polysaccharide fraction (PGP IV) isolated from Platycodon grandiflorum significantly stimulates the proliferation of mouse monocyte-macrophage leukemia cells (RAW264.7) and enhances their phagocytic capacity in a dose-dependent manner. Higher doses of PGP IV treatment can induce the secretion of nitric oxide (NO), tumor necrosis factor (TNF), and interleukins (ILs). Astragalus polysaccharide inhibits the invasiveness of lung cancer cells by reducing the secretion of macrophage migration inhibitory factor. In vitro cell culture studies using Ganoderma lucidum spore polysaccharide (GLSP) on primary macrophages extracted from mice have confirmed that GLSP promotes M1 polarization of primary macrophages and upregulates the expression of cytokines such as TNF-α, IL-1β, IL-6, and TGF-β1.

2.Impact on Natural Killer Cells

Natural killer cells (NK cells) are vital immune cells that naturally exist within organisms and function as non-specific immune killing cells. They play a crucial role in the immune processes of the body against parasitic infections, antitumor, and antiviral defenses. NK cells possess dual functions of immune regulation and cytotoxicity. Studies have shown that Radix Polygoni Multiflori polysaccharide (a polysaccharide derived from the root of a traditional Chinese medicinal plant) can effectively activate NK cells and promote the proliferation and differentiation of T cells, leading to a significant increase in the number of cytokines in the body. By enhancing the activity of NK cells, polysaccharides cause target cells such as YAC-1 to lose their adherence function and release intracellular lactate dehydrogenase (LDH), lithium lactate dehydrogenase, and nicotinamide adenine dinucleotide (NADH) reduction. Subsequently, through the reduction of hydrogen-carrying phenazine methosulfate sulfate and the reduction of iodonitrotetrazolium chloride to formazan-like compounds, NK cells mediate the killing of tumor cells and virus-infected cells via cytotoxicity, thereby enhancing the body's non-specific immune capacity.

Studies have found that fucoidan obtained using the water extraction method can stimulate RAW264.7 mouse macrophages to secrete nitric oxide (NO), TNF-α, IL-1β, and IL-6. Furthermore, it activates NK cells through the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways, promoting the release of TNF-α, TNF-γ, granzyme-B, and perforin, thereby enhancing the killing activity of NK cells. When administered therapeutically to immunosuppressed mice, shiitake mushroom polysaccharide can enhance the killing activity of NK cells and immunoglobulin M (IgM) secretion within a certain concentration range. Additionally, when shiitake mushroom polysaccharide is administered in the form of polysaccharide-alginate microcapsules, it activates NK cells synergistically, increasing the killing effect on colon cancer cells. Lonicera japonica polysaccharide (LJP) significantly increases the body weight, organ indices, and secretion of IL, TNF, and IFN-γ cytokines in mice treated with dextran sulfate sodium (DSS). It also elevates the level of secretory immunoglobulin A (SigA) and enhances the activity of NK cells and cytotoxic T lymphocytes (CTLs).

The Impact of Plant Polysaccharides on Adaptive Immune Response

Adaptive immune response, also known as acquired immune response, is a defense mechanism gradually developed by organisms during their long-term germline evolution. This response enables the body to effectively eliminate antigenic foreign substances by distinguishing between "self" and "non-self," thereby maintaining the relative stability of the internal environment. Based on the types of cells and mechanisms involved in the immune response, adaptive immune response can be classified into T lymphocyte-mediated cellular immune response and humoral immune response, which is mediated jointly by T and B lymphocytes.

1. Impact on Cellular Immunity

T cells are lymphocytes that participate in cellular immunity. Upon stimulation by antigens, they transform into sensitized lymphocytes and exhibit specific immune responses. These immune responses can only be transmitted through sensitized lymphocytes, hence the term cellular immunity. Research has revealed several effects of plant polysaccharides on cellular immunity:

Angelica sinensis polysaccharide (ASP): In treating mice with aplastic anemia, ASP has been found to increase the activity of regulatory T cells (Tregs) by altering the P-p38/p38 and Treg/Th17 ratios.

Grifola frondosa polysaccharide: By enhancing the immune functions of CD4+ T cells and CD8+ T cells, as well as promoting the secretion of cytokines like IL-2 and TNF-α, this polysaccharide inhibits tumor growth.

Astragalus polysaccharide: Administration of Astragalus polysaccharide to mice with B16 melanoma increased the ratios of CD4+ and CD4+/CD8+ T cells, reduced the number of myeloid-derived suppressor cells in melanoma mice, and enhanced immune function. Furthermore, when combined with PD-L1 antibody in treating Lewis lung cancer mice, Astragalus polysaccharide increased spleen and thymus indices, CD4+ T cell proportions, and CD4+/CD8+ T cell ratios, improved T cell-related cytokine levels, and enhanced the tumor-killing ability of splenic lymphocytes.

Okra raw polysaccharide extract (ORPE): In mice with DEN-induced liver cancer, ORPE directly inhibited the accumulation of Tregs and macrophage activation, balancing the number of effector T cells. At low doses, ORPE promoted CD8+ T cell activation, and increased IL-2 levels at all doses tested. These results indicate that ORPE possesses dual functions as both an immunosuppressant and an immunostimulant.

2. Impact on Humoral Immunity

Humoral immunity refers to the immune mechanism that protects the body through the production of antibodies by plasma cells. The cells responsible for humoral immunity are B cells, which transform into plasma cells upon antigen stimulation and synthesize immunoglobulins. Immunoglobulins that can bind to target antigens are known as antibodies. Antibodies are glycoproteins secreted by plasma cells after B cells undergo proliferation and differentiation in response to antigen stimulation. They primarily exist in bodily fluids such as serum and participate in specific antigen-antibody reactions. The level of antibody production is one of the primary indicators of non-specific immune function in the body.

Polysaccharides themselves can not only elevate serum antibody levels in mice by regulating the phagocytic capacity of macrophages and serum hemolysin levels but also enhance the secretion of IL-2 by splenic lymphocytes in vitro, increasing their participation in antibody responses and thereby improving humoral immune function and enhancing overall immune activity. Furthermore, polysaccharides can increase the secretion levels of antibody-active immunoglobulins and C3, C4 complement levels in the serum of rats with impaired immune function. When these two factors act synergistically, they exhibit significant effects in killing pathogenic microorganisms.

Research has demonstrated that Hippophae rhamnoides polysaccharide (HRP) possesses antioxidant and immunomodulatory effects. When administered to porcine jejunal epithelial cells (IPEC-J2) within a certain concentration range, HRP can elevate the levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), IL-1β, IL-2, IL-6, IL-8, and TNF-α, as well as increase the relative mRNA levels in IPEC-J2 cells. Simultaneously, the levels of IgM, IgA, and IgG increase with rising HRP concentrations.

On the other hand, Poria cocos polysaccharide (PCP) has been shown to significantly upregulate the surface expression of major histocompatibility complex class II (MHC-II), CD40, CD80, and CD86 in the blood of C57BL/6 mice, and promote the production of IL-6 and IL-12p40. When PCP is used in combination with ovalbumin (OVA) for subcutaneous immunization, it significantly enhances the serum levels of OVA-specific IgG, IgG2a, and IgG1 antibodies. Furthermore, PCP increases the number of CD8+ and CD4+ T cells secreting OVA-specific IFN-γ, promotes CD8+ T cell proliferation, and upregulates the production of IFN-γ and IL-2 cytokines by T helper 1 (Th-1) cells.

References

[1] Lin Zhimin, Xiao Jian. Research Progress on the Immunomodulatory Effects of Plant Polysaccharides [J]. Labeled Immunoassays & 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.