Perspective Chapter: Phytocompounds as Immunomodulators

Abstract

Healthy operation of every organ depends on immune cells. T-cells, B-cells, and natural killer cells that control the immune homeostasis. Immunotherapy includes the process by which immune cells are immunomodulated. Immunological responses can be induced by immunostimulants, amplified by immune boosters, attenuated by immunomodulators, and prevented by immunosuppressive agents, according to therapeutic techniques. The over-activation of the immune system is mostly to blame for the rise of chronic immunological illnesses such as viral infections, allergies, and cancer. Immunomodulators may also be used to control the severity of long-term immunological diseases. Additionally, it is discovered that these immunomodulator-acting proteins represent prospective molecular targets for the control of the immune system. Furthermore, it is well known that organic molecules like phytocompounds have the ability to bind to these locations and affect the immune system. Curcumin, quercetin, stilbenes, flavonoids, and lignans are examples of specific phytocompounds shown to have immunomodulatory properties to address immunological diseases.

1. Introduction

A healthy immune system is beneficial for every organ. The self-regulation of T-cell, B-cell, and natural killer cell activity creates the immune system’s homeostasis. The functioning immune systems serve as a connected network in the body, defending the organs against numerous immunological diseases. Additionally, it recognises invasive pathogens like bacteria, viruses, and parasites and reacts quickly to them [1]. The innate immune system and the adaptive immune system are the immune system’s two main subsystems. The innate immune system responds in a programmed way to a wide range of immunologically active proteins and immune stimuli. In comparison, the adaptive immune system responds sequentially to each stimulus by identifying the chemicals the immune cells use to operate [2]. Immunological disorders, inflammatory reactions, and the development of cancer can all be brought on by the dysregulation of immune activities. Chronic immunodeficiency has also been linked to an increase in infections that can be fatal [3]. Genetic changes are also related to some immune illnesses. These severe immunological conditions include acquired immunodeficiency syndrome (AIDS) [4]. Type 1 diabetes, rheumatoid arthritis, Hashimoto’s thyroiditis and systemic lupus erythematosus are just a few major autoimmune disorders that are commonly treated using immunomodulatory medications [5].

However, the excellent health of a patient with chronic immunological problems depends on a functioning immune system. Numerous organic substances, including polyphenols, alkaloids, polysaccharides, glycosides, lactones, terpenoids, and flavonoids, have been shown to modify immune cells and have immunomodulatory effects [6]. The essential immunological cells it interacts with are macrophages, dendritic cells, lymphocytes (T- and B-cells), and natural killer (NK) cells. The primary immunomodulatory effects are brought about by secreted antibodies against various pathogens and maintain immunological homeostasis [7]. Our bodies’ immune systems create a self-defence strategy to stave off illnesses from numerous pathogens. Innate and adaptive immune cells work with anatomical and physiological barriers to form the human body’s three layers of protection against pathogens. Saliva, epidermis, mucous membranes, low stomach pH, and other secretions are among the anatomical and physiological barriers that make up the immune system’s first line of defence against pathogens. Other bodily fluid discharges and the stomach’s low pH level can also easily interact with immune cells [8]. The second level of defence begins with inflammatory cells like mast and macrophage cells and uses complement system formation and immunomodulatory action to establish innate immunity. It covers the roles of basophils, NK cells, mast cells, neutrophils, eosinophils, macrophages, dendritic cells, and natural killer T cells in immunological activity [9]. Twenty serum glycoproteins make up the complement system, where the main immunomodulatory effects begin. Additionally, three pathways—the lectin pathway (mannose-binding lectin reaction), the alternative pathway (bacterial endotoxin reaction), and the classical pathway (antigen–antibody reactions)—are involved in the activation of the complement system. Circulatory complement-3 (C3) proteins are involved in every pathway and are crucial for immunomodulatory effects [10]. Through T and B cells, the first and second levels of defence systems generate non-specific immune responses, known as adaptive immunity. This is an antigen–antibody-associated immune cell-specific response and forms the third level of the immune defence system [9]. The primary innate and adaptive immune system function and their cells are illustrated in Figure 1.

Figure 1.

Immune system traits and functions of different innate and adaptive immune cells. There are two types of immunity in the immune system: Innate immunity and adaptive immunity. Among the participants in the innate immune system are dendritic cells, macrophages, mast cells, granulocytes (neutrophils, eosinophils and basophils), NK cells, NKT cells and δγ T cells. The pink grid lists each cell type’s primary fuctions. B cells, CD4⁺ T cells, CD8⁺ T cells and other cells are all part of the adaptive immune system. Under various microenvironments specialised by interacting cytokines and chemokines, as well as unique activation of particular transcription factors, CD4⁺ T cells can develop into Th1, Th2, Th17 and inducible Treg (iTreg) cells. CD8⁺ T cells are in charge of verifying cytotoxicity against cancerous or virus-infected cells. Treg cells are often divided into two types, natural Treg (nTreg) cells and iTreg cells. To maintain immunological homeostasis, they can control particular immune responses, including immune tolerance. Abbreviations: TCR, T cell receptor; MHC-II, major histocompatibility complex class II; NK, natural killer cells; NK T cells, natural killer T cells; Th1, T-helper type 1; Th2, T-helper type 2; Th17, T-helper type 17; IL-2, interleukin-2; IL-13, interleukin-13; IL-17, interleukin-17; IL-22, interleukin-22.

Pathogen recognition receptors (PRRs) are used in the innate immune system to identify the infection pattern. Pathogen-associated molecular patterns (PAMPs) detect the microbial components of molecular proteins. The PAMPs consists of bacterial parts such flagella, nucleic acid components, and lipopolysaccharide [7]. PPR families include cytoplasmic proteins like NOD-like receptors (NLRs), retinoic acid-inducible gene-I-like receptors (RLRs), and transmembrane proteins like C-type lectin receptors (CLRs), and toll-like receptors (TLRs) [11]. Antigen-presenting cells, such as dendritic cells (DCs), B cells, and macrophages, make up non-specific immune systems. In order for cytotoxic T-cells and B-cells, as well as non-antigen specific macrophages, NK cells, and eosinophils, to perform their essential roles, dendritic cells must first deliver the antigens to a group of domain-4 (CD4)-T-helper cells. Tumour necrosis factor-α (TNF-α) and cytokines (IFN-γ) are generated during the proliferation of DCs as a result of immunological responses [12]. In adaptive immunity, a defence mechanism is formed by the injected agents against the particular pathogens and stop infections. It is also referred to as acquired immunity. It primarily affects T and B cells, resulting in a cell-mediated immunological response and antibody generation. This adaptive immune response is primarily supported by CD4+ T-lymphocytes (helper T-cells) and CD8+ T-lymphocytes. Additionally, these T-helper cells are developed from Type-1 T helper (Th1) and Th2 cells, and they secrete IFN-γ and IL-5 to improve adaptive immune responses [13].

1.1 Immunomodulators

Immunomodulators include immunostimulants and immunosuppressive medications [14]. The efficient and effective homeostasis that the healthy immune system generates keeps the human body free from disease. Additionally, it governs the cellular signalling molecules as the favourable host responses and has strong communication of cells via signal transduction pathways. Immune cell-acting substances can either boost or inhibit immune cells’ typical efficiency and function when administered endogenously or exogenously. It is sometimes referred to as host responses for immunomodulatory actions [15]. This immunity prevents chronic immunological disorders such as AIDS, cancer, autoimmune diseases, and allergic reactions [14].

Immunostimulants, immunoadjuvants, and immunosuppressants are the three categories that comes under immunomodulators. Immunostimulants are substances that cause the immune system’s cells to become active. Vaccines operate according to these principles to enhance the specific immunostimulant actions. Immune response to specific pathogenic antigens is strengthened by it. Some reports have shown that natural substances, such as phytocompounds, are known to have general immunostimulant effects. Cancer and other chronic infections like those that cause immunodeficiency disorders are also said to be attenuated. Interferon-alpha (IFN-alpha) and granulocyte colony-stimulating factors are two examples of endogenous immunostimulants involved in developing immunostimulant effects [16]. Moreover, FDA also describes the immunoadjuvants therapy category for immunological illnesses. The conjugation of immunoadjuvants with a vaccination antigen results in the augmentation and potentiation of target proteins for the particular immune response against the antigen. Histamine, tuftsin, interferons, IL-1, transfer factor, and IL-1 are endogenous natural adjuvants. It can intensify the targeted antigen’s interactions with the host immune system and induce phagocytosis [17, 18].

To lessen overly strong immunological reactions, immunosuppressants are also necessary. Excessive immune cell function can cause serious systemic consequences. Immunosuppressive medications are necessary for various therapeutic situations, such as organ transplantation (pre and post-surgical conditions). A few immunosuppressive drugs momentarily weaken immune cell functions. Along with these conditions, it is also used to treat rheumatoid arthritis, myasthenia gravis, and Grave’s disease. Additionally, it manages graft rejection reactions in tissue (skin) and cells (bone marrow transplant) [17]. Similarly, some natural phytoconstituents suppress the immune system and treat immunological diseases by interfering with the host cell’s molecular communication pathways.

2. Phytocompounds as immunomodulators

More than 5000 years of history are found for medications made from natural products, compared to a few hundred years for Western medicine. More than 85,000 plant species have been used medicinally around the world. According to the WHO, up to 80% of people worldwide, primarily in developing nations, rely on herbal remedies to cure a various illnesses, including immunological disorders [19]. Additionally, about 30% of all FDA-approved medications have a botanical origin [20]. Based on this data, it’s critical to look into traditional phytomedicines’ chemical makeup to assess their potential as immunomodulatory agents for immunological diseases. The chemical compositions, molecular targets, and related illnesses of the representative phytocompounds are summarised. The classification of phytochemicals is given in Figure 2.

Figure 2.

Classification of phytochemicals.

Numerous pharmacological effects can be attributed to phytocompounds including immunomodulatory effects. Several phytoconstituents, including polyphenols like stilbenes, resveratrol, hydroxycinnamic acids, and curcumin; flavonoids like epigallocatechin gallate (EGCG) and quercetin; alkaloids like berberine (BBR), & colchicine; terpenoids like andrographolide, & oleanolic acid; polysaccharides like pectin [21, 22] are found to act on immune system. They modulate the activity of a variety of immune cells, including dendritic cells (DCs), lymphocytes, neutrophils, monocytes, macrophages, basophils, mast cells, eosinophils, and natural killer (NK) cells. It frequently controls phagocytic cells, including neutrophils, monocytes, macrophages, basophils, mast cells and eosinophils that secrete inflammatory mediators and natural killer (NK) cells [23].

It is evidenced experimentally that the phytocompounds alter a number of the molecular targets of the immune cell signalling mechanism. In immune cells, they also modify the release of soluble substances and these include transcription factors and interleukins (IL) such as IL-2, IL-4, IL-6, IL-12, IL-17 and immunoglobulins (Igs) [24]. The transcription factors nuclear factor-κB (NF-κB) and inhibitor κB (I-κB) are frequently used to control the activity of immune cells and have immunomodulatory effects. It also phosphorylates the c-Jun N-terminal kinases (JNK/Jun) pathways, degrades the inhibition of the NF-κB p65 subunit and I-κB, increases the levels of reduced glutathione (GSH) and superoxide dismutase (SOD) dependent on T-lymphocytes, and collaterally enhances immune responses through the expression of TLR4 and upregulation of cytokine genes [25]. Additionally, different immune cells and their cell signals behave in varied ways based on the pathophysiological circumstances of various body systems. Therefore, a clear, precise mechanism and the unique activity of phytoconstituents on immune cells must be thoroughly studied [26]. The following sections have detailed the specifics of phytoconstituents for the immunomodulatory mechanism of action.

2.1 Polyphenol

Any compound, including functional derivatives (esters, glycosides, etc.), with an aromatic ring and one or more hydroxyl substituents is referred to as a “polyphenol” or “phenolic”. Polyphenols in foods or natural health products come from one of the main classes of secondary plant metabolites derived from tyrosine or phenylalanine. They are widely found in fruits, vegetables, beverages and cereals [27].

2.1.1 Stilbene derivatives

The phenolic compounds known as stilbenes have two aromatic rings connected by an ethene bridge (C6–C2–C6) [28]. Trans-3,5,4′-trihydroxystilbene, also known as resveratrol, is a well-known phytoalexin of the stilbene class. It is a natural substance found in grapes, berries, and other traditional Chinese medicines like Polygonum cuspidatum. It is known to work by modulating a various distinct pathways to produce its effects [29]. Numerous cell-signalling molecules connected to inflammation have been demonstrated to bind to resveratrol. It inhibits cyclooxygenase-2 (COX-2) protein expression in mammary epithelial cells and activates phorbol-12-myristate-13-acetate (PMA) to control the protein kinase C (PKC) transduction pathway for immunomodulatory effects [30]. Additionally, it inhibits p65 subunit phosphorylation, IκBα kinase phosphorylation, and NF-κB for DNA activities, all of which are implicated in immunological actions [31, 32]. Moreover, it blocks the activator protein-1 (AP-1) that is in charge of immunological effects [33]. Experimental evidence suggests that resveratrol blocks the lipopolysaccharide (LPS) induced NF-κB p65 nuclear translocation, as well as the down-regulation of IL-6, nitric oxide, IL-18, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMP-2 and MMP-9) secretion in E11 cells. Furthermore, it inhibits THP-1 and U937 monocyte migration in inflammatory areas by immunological reactions [34]. Resveratrol dramatically decreases the expression and activity of inducible nitric oxide synthase (iNOS) [35].

2.1.2 Hydroxycinnamic acids

Another name for hydroxycinnamic acids is hydroxycinnamates (i.e., curcumin, and p-Coumaric acid). Chemically, it belongs to the phenylpropanoids or class of aromatic acids. It is a hydroxy derivative of cinnamic acid, and has a C6-C3 skeleton. It appears as α-Cyano-4-hydroxycinnamic acid in food, including fruits, vegetables, and cereals, and has the potential to scavenge free radicals and guard against inflammation, dyslipidemia, insulin resistance, diabetes, and cardiovascular illnesses [36]. The molecular function of hydroxycinnamic acids is to improve the host immune response and lessen harm to the body’s essential organs [37]. The active component of Curcuma longa is curcumin, a hydroxycinnamic acid derivative and is known as diferuloylmethane chemically [38]. The anti-platelet, anti-inflammatory, hepatoprotective, anti-cancer, and anti-arthritic properties of curcumin make it a popular treatment option in Ayurvedic medicine [39]. It is also recognised to have immunomodulatory effects. Experimental evidence suggests that it inhibits the transcription factors such as cytosine-cytosine-adenosine-adenosine-thymidine (CCAAT)/enhancer-binding protein (C/EBP), CTCF, β-catenin, heat shock factor-1, Notch-1, hypoxia-inducible factor-1 (HIF-1), early growth response-1 (Egr-1), AP-1, signal transducers and activators of transcription (STAT)-1, 3, 4, 5 and NF-κB [40]. Additionally, AP-1 and NF-κB, which are immune cell transcription factors, are suppressed by curcumin to provide the anti-tumour effect [41].

2.1.3 Flavonoids

Flavonoids are one of the most prevalent naturally occurring substances in all vascular plants. At least 6500 naturally occurring flavonoids have been discovered, and nearly all plant tissues are capable of producing flavonoids. The 15 carbon atoms that make up the essential backbone of flavonoids (C6-C3-C6) define them. They are typically divided into seven classes based on their chemical makeup: flavones, flavanones, flavonols, flavanonols, isoflavones, flavanols, and anthocyanidins [42]. They often take the form of a flavonoid glycoside or an aglycone. While aglycones are primarily found in woody tissues, flavonoid glycosides are primarily found in leaves, flowers, or fruits. Both flavonoid aglycones and glycosides can be found in seeds. Flavonoids have long been known to have anti-inflammatory, anti-hepatotoxic, anti-atherogenic, anti-osteoporotic, anti-allergic, and anti-cancer properties, in addition to their well-known antioxidant activity [43]. Quercetin is a flavonol that is present in foods including grapes, tea, onions, apples, and leafy green vegetables [44]. The most well-known active ingredient in tea is epigallocatechin gallate (EGCG), a potent antioxidant. It can affect phase I and phase II enzymes in addition to being a potent anti-inflammatory and antioxidant that guards the body against the damaging effects of free radicals [45]. The inhibition of transcriptional factors (such as NF-kB and AP-1) and the elevation of Nrf-2, which results in a decrease in pro-inflammatory mediators, are thought to be the anti-inflammatory modes of action of quercetin and EGCG [46]. These properties have led researchers to consider using these chemicals to treat inflammatory illnesses, ageing, neurological disorders, inflammatory bowel diseases, cancer, and diabetes.

2.2 Terpenoids

Terpenoids, also known as isoprenoids, comprise five carbon isoprene units (C5H8). It is a broad and diversified family of naturally occurring chemical compounds from the 5-carbon molecule isoprene. The term terpenes are used as another name for the polymers of isoprene. For terpenes, oxygen is the primary functional group. Quite a few pharmacological effects are present [47]. Found in several conventional herbal remedies, including eucalyptus leaves, the flavours of cinnamon, cloves, and sunflowers, as well as foods like ginger and tomatoes. The bioactive components of terpenoids include citral, menthol, camphor, salvinorin A, cannabinoids, ginkgolide, bilobalide, and curcuminoids [48, 49]. In addition, the bioactive immunomodulating drugs andrographolide and oleanolic acid are active. Andrographolide is a bicyclic diterpenoid lactone compound. It is an official Chinese herbal medicine component and has strong anti-inflammatory properties. Additionally, it can be found in the leaves of Andrographis paniculata and is used to treat rheumatoid arthritis, laryngitis, and diarrhoea. Nitric oxide (NO) generation is known to be reduced, and iNOS expression is inhibited by andrographolide in RAW 264.7 cells [50]. According to in-vitro research, andrographolide regulates the activity of immune cells like macrophages and microglia, which produces immunomodulatory effects by reducing the levels of TNF-α, COX-2, IL-12, iNOS, and PGE2 proteins [51]. Additionally, it actively modifies the virality of the influenza virus by downregulating the genes for the JAK/STAT signalling and NF-kB signal pathways [52].

Oleanic acid (3β-hydroxy-olea-12-en-28-oic acid) is another name for oleanolic acid. It is naturally related to betulinic acid and contains a pentacyclic triterpenoid moiety. Olea europaea, Rosa woodsii, Prosopis glandulosa, Phoradendron juniperinum, Syzygium claviflorum, Hyptis capitata, Mirabilis jalapa, and Ternstroemia gymnanthera are a few examples of foods and plants that contain it. It is composed of an aglycone component for triterpenoid saponins and a free acid group chemically and has historically been used for its cardiotonic, analgesic, anti-inflammatory, and hepatoprotective effects [53]. Oleanolic acid is known to have immune-modulatory effects by causing eukaryotic cells to release high mobility group box-1 protein (HMGB1) and macrophages to release C-reactive protein, endotoxins, and TNF-α. Through the secretion of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α produced by macrophages, this extracellular HMGB1 acts as a potent immune stimulator [54]. Numerous immune-inflammatory diseases, including disseminated intravascular coagulation, atherosclerosis, sepsis, rheumatoid arthritis, xenotransplantation, and periodontitis, are known to have these immunological reactions. Oleanolic acid also prevents the LPS-induced activation of macrophage-like RAW264.7 cells by reducing the levels of HMGB1 proteins [55]. It is discovered to interact with a cyclooxygenase-2(COX2)-dependent mechanism to stimulate prostaglandin I2 (PGI2) release by human coronary smooth muscle cells [56]. Since it manages immunological problems, it is regarded as an immunomodulator.

Carotenoids are pigmented tetraterpenes, since they have strong light absorption and brilliant colour. They typically have a 40-carbon polyene chain and are made up of eight isoprene units. This nonradiative energy transfer mechanism enables them to absorb extra energy from other molecules [57]. Carotenoids are naturally occurring, lipid-soluble pigments that give host plants and animals their vibrant colour. Plant carotenoids may be crucial to maintaining human health [58]. They can act as potent antioxidants and are thought to treat several chronic illnesses, including cancer, osteoporosis, and cardiovascular disease. Some carotenoids, including lutein, β-carotene, and lycopene, may be able to reduce some inflammatory responses by modulating redox-sensitive signalling pathways like NF-kB and ROS [59, 60, 61]. The most prevalent cyclic tetraterpene and most potent pro-vitamin A in nature are β-carotene. It can be turned into vitamin A and is stored in the liver [57]. Lutein, a dihydroxy derivative of β-carotene and a standard component of many fruits and vegetables as well as egg yolks, is one of the lipophilic xanthophylls. It can prevent age-related macular degeneration, guard against oxidative stress, and have a neuroprotective impact on retinal inflammation [62, 63]. Lycopene, an additional acyclic tetraterpene, is the most prevalent carotenoid in the human body [58]. It is primarily found in fruits and vegetables that are red in colour. Since lycopene is a more potent antioxidant than vitamin E, it helps shield cells from free radical damage when there is oxidative stress. It has also been asserted that it lowers the chance of several chronic illnesses, including cardiovascular problems, RA, and atherosclerosis [57, 58]. These carotenoids with antioxidant properties may be developed into immunomodulators in the future.

2.3 Alkaloids

The most valuable and essential plant compounds are alkaloids, which are also powerful medicinal agents [64]. The alkaloid family is the largest class of secondary plant chemicals with one or more nitrogen atoms, typically combined as part of a cyclic structure, which consists of around 5500 identified compounds. At least one nitrogen atom with a basic nucleus is present [65]. Other elements found in alkaloids include carbon, hydrogen, oxygen, sulphur, chlorine, bromine, and phosphorus. These organic substances are neutral or only slightly acidic. A few synthetic substances have structure similar to natural alkaloids. Numerous creatures, including fungus, bacteria, mammals, and plants, contain alkaloids [66]. It has numerous medicinal effects, including anti-malarial, anti-asthmatic, anti-cancer, cholinomimetic, vasodilatory, anti-arrhythmic, analgesic, anti-bacterial, and anti-hyperglycemic effects. Several alkaloids have stimulant and psychoactive effects on the central nervous system (CNS) [67]. Additionally, it has immunomodulatory effects. Immune effector cells trigger the main immunomodulatory pathways of alkaloids to cause autoimmune responses [68]. It interacts with the forskolin proteins, lysosomes, phagocyte vacuoles, and neutrophil, monocyte, and macrophage cytoskeleton filaments. In addition, it triggers the innate immune response by causing macrophages to perform phagocytic functions [69]. Moreover, active antigen-presenting cells (APCs) i.e. macrophages, contribute to the production of adaptive immune responses [70]. Potent alkaloids i.e., berberine (BBR) and colchicine are identified as potential immunomodulatory drugs.

Berberine (BBR), an isoquinoline alkaloid, is present in several Berberis species. Its chemical name is 5,6-dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxolo[5,6-a] quinolizinium compound. It has anti-diabetic, hepatoprotective, hypolipidemic, cancer-preventive, anti-hypertensive, anti-oxidant, anti-inflammatory, anti-depressant, anti-diarrheal, and anti-microbial effects [71, 72, 73]. Multiple mechanisms of action are used to create these pharmacological effects. It interacts with multiple cellular kinases and signalling pathways. Some routes of the actions are interlinked with immunomodulatory pathways i.e., activation of nuclear factor erythroid-2-related factor-2 (Nrf2), MAPKs, NF-κB, & AMPK pathways; and expression of sirtuin 1 (SIRT1), & deacetylation of transcription factors of forkhead box O (FOXO) proteins [74]. In studies, BBR also lowers levels of proinflammatory cytokines such IFN-γ, IL-17, IL-6, and TNF-α, which results in immunomodulatory effects in non-obese diabetic (NOD) mice [73]. The overexpression of NADPH oxidase 2/4 is also downregulated, which results in antioxidant effects [75]. Furthermore, BBR stimulates Nrf2 activities, which increases the production of antioxidant enzymes such as NADPH quinine oxidoreductase-1 (NQO-1) and heme oxygenase-1 (HO-1). Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), P38, and AMPK pathways are a few of the different cell signalling pathways that are promoted by Nrf2 [76]. As a result, it can be employed as an immunomodulatory agent to treat autoimmune diseases.

A significant natural alkaloid called colchicine is derived from the Colchicum autumnale plant (Colchicaceae family). Colchicine is a medication that has anti-inflammatory effects and is used to treat various inflammatory diseases including pericarditis, gout, and familial Mediterranean fever. It is known to impede microtubule polymerisation and reduce the growth of several types of cancer cells as its primary mechanism of action. Additionally, it has been discovered to decrease immunological responses such as neutrophil chemotaxis, lysosome breakdown, and leukocyte adhesiveness [77]. The immune cell signals i.e., nucleotide-binding and oligomerization domain (NOD), leucine-rich repeat proteins (LRR)-containing protein 3 and pyrin domain proteins [NLRP3 sensors] is suppressed by colchicine as well. SARS-CoV-2 proteins are also capable of initiating and energising comparable pathways. The therapy of COVID-19 with colchicine has tragically failed [78]. Moreover, it inhibits the production of leukotriene B4, neutrophil chemotactic factor and IL-1, which cause the immune cell regulatory action [79, 80, 81]. According to a literature review, colchicine can restrict procollagen synthesis, increase collagenase activity, and block mast cell release of histamine. It can also reduce the production of TNF-α that is caused by LPS [82, 83, 84]. Hence, autoimmune illnesses can be managed using their immunomodulatory effects.

2.4 Glycosides

The secondary metabolites of plants that contain sugar are called glycosides, a portion to which non-sugar portions are joined. The binding between the sugar and nonsugar moiety leads to hemiacetal formation. It includes the alcoholic or phenolic hydroxyl group of nonsugar and the aldehyde or keto group of the sugar moiety. These agents play numerous beneficial activities in animals and humans; however, many plants accumulate these chemicals in an inactive form which can be activated by the action of enzymes in the body [85]. Glycosides may be classified depending upon the glycone and aglycone moieties, such as glucoside, fructoside, α-glycosides and β-glycosides. Amygdalin and scrocaffeside-A are identified as primary bioactive immunomodulating agents. These substances primarily work to stimulate the immunological, cardiac, and central neurological systems. Furthermore, glycosides also show substantial antibacterial effects [86].

The bitter almond, apricot, plum, apple, and peach fruit kernels contain amygdalin, a cyanogenetic glycoside. Leukoderma, colorectal cancer, emphysema, leprosy, bronchitis, and asthma are all conditions frequently treated by amygdalin [87, 88]. By controlling T-cells, amygdalin has been shown to suppress inflammatory reactions and enhance immunomodulatory effects [89]. Additionally, it activates caspase-3, which suppresses Bcl-2-like protein 4 (Bax, proapoptotic protein) and B-cell lymphoma 2 (Bcl-2, an antiapoptotic protein) [88]. It stops the metastases of cancer cells via prevention of β1 and β4 integrins expression leading to suppression of the Akt-mediated mammalian target of rapamycin (mTOR) pathway (immunomodulatory mediators). Moreover, it lowers the β-catenin, integrin-linked kinase (ILK), and focal adhesion kinase (FAK) expression in immune cells [90]. Consequently, amygdalin is also an immunomodulatory agent.

Picrorhiza scrophulariiflora roots contain the caffeoyl glycoside known as scrocaffeside-A. It effectively heals leukoderma, inflammatory illnesses, gastrointestinal & urinary disorders, scorpion stings, and snake bites [91, 92]. Additionally, it controls the immunological responses of splenocytes by triggering concanavalin-A and LPS interactions [93]. According to an in vitro investigation, scrocaffeside-A increases CD4/CD8 population and cytokine production in splenocytes, which activates peritoneal macrophages and natural killer cell activity. Furthermore, it has been observed that scrocaffeside-A exposure increases the production of IFN-α, IL-2, IL-4, and IL-12 in cultured splenocytes. It suggests that scrocaffeside-A stimulates the host’s immune system [94] and as a result, scrocaffeside-A is regarded as an immunomodulating substance.

2.5 Polysaccharides

Polycarbohydrates are another name for polysaccharides and are present in many foods. Its constituent monosaccharide units and glycosidic connections make up the long-chain polymeric carbohydrates. With the aid of amylase enzymes, it rapidly reacts with water through hydrolysis. This enzyme makes the constituent sugars i.e., monosaccharides, and oligosaccharides from polysaccharides [95]. Biologically, it is stored as starch, glycogen, galactogen, cellulose, and chitin. It is found in various plants including marine sources. Marine polysaccharides are used as medicine for variable disorders. Marine sources of polysaccharide have enriched contents of organic compounds like terpenoids, polyethers/ketides, lipo-glycoproteins, peptides, and polysaccharides [96]. It acts on various cell surface receptors altering cell proliferation and differentiation. Furthermore, it possesses immunomodulatory effects [97]. Pectin and Acemannan are also recognised as important bioactive immunomodulating substances.

The complex polysaccharide molecule known as pectin contains d-galacturonic acid monomers that have been esterified and connected by α-(1–4) chain [98]. In its typical state, pectin functions as an adsorbent and rapidly binds to various poisons, germs, and irritants in the intestinal mucosa. It lowers the pH in the intestinal lumen and has calming effects. The digestive system’s alkaline environment is treated using modified pectin. Citrus pectin and modified citrus pectin, which are plant-based pectins, are known to have immunomodulatory effects by increasing the pro-inflammatory cytokines such as IFN-γ, IL-17, and TNF-α [99]. Pectin also inhibits the pro-inflammatory TLR2-TLR1 pathway, which is how it blocks the toll-like receptor 2 (TLR2) [100]. Specific polysaccharides produce immunomodulatory effects and influence immune cell function. Additionally, interactions between T-cells, monocytes, macrophages, and polymorphonuclear lymphocytes have altered innate and cell-mediated immunity through the influence of polymers of polysaccharides [101]. Because of this, it is utilised as an immunomodulatory medication to treat immunological diseases.

Acemannan, a mucopolysaccharide molecule, is widely distributed in aloe vera leaves. It has the chemical name β-(1,4)-acetylated soluble polymannose. It induces IFN, IL-1, TNF, and prostaglandin E2 release from activated macrophages. Additionally, it improves the control of macrophage phagocytosis, T-lymphocyte activity, and non-specific cytotoxicity. Potential anti-oxidant, antiviral, immunostimulant, antineoplastic, wound-healing, bone-proliferation, and neuroprotective effects are present [102]. It stimulates the generation of nitric oxide and macrophage-mannose receptors, which activate immune cells like macrophages [103]. Furthermore, through IFNγ-associated suppression of bcl-2 (B-cell lymphoma 2) expression, acemannan stimulates the RAW 264.7 cells [104]. Treat immunological disorders, it is regarded as an immunomodulatory agent.

2.6 Tannins

Tannins are substances with a high molecular weight that are water soluble and frequently found in plants as a complex with proteins, polysaccharides, and alkaloids. Depending upon their solubility or hydrolysis product, tannins are divided into hydrolysable tannins, proanthocyanidins, phlorotannins. Gallic acid esters are used to produce hydrolysable tannins. Phlorotannins are formed from phloroglucinol, obtained from brown algae, and condensed tannins are a combination of polyhydroxy flavan-3-ol monomers. Walnuts, peaches, berries, apples, and grapes are among the significant sources of tannins [105]. Numerous preclinical studies have shown their immunomodulatory properties.

Punicalagin (PCG), an ellagitannin, has several health benefits. According to Lee et al. investigation, the immunosuppressive properties of PCG derived from Punica granatum depend on its impact on the nuclear factor of triggered T cells (NFAT). Data showed administration of PCG inhibited leukocyte response, IL-2 expression, and CD3 + T cell infiltration. Moreover there is some evidence that PCG may be a free radical scavenger and thus can be used as potent immunosuppressive drug [106]. Reddy Reddana did yet another study on chebulagic acid’s (CA) immunosuppressive properties, derived from Terminalia chebula, on LPS-induced RAW 264.7 cell line. The expression of IL-2, TNFα and ROS production was considerably reduced after treatment with CA. A dose-dependent trend was also observed in the inhibition of NF-κβ activation, p38, JNK, and ERK 1/2 phosphorylation [107]. Furthermore, Corilagin extracted from T. chebula showed the neuroprotective activity by downregulating the H₂O₂ stimulated PC12 cells death [108].

2.7 Saponins

The group of naturally occurring glycosides known as saponins is abundantly found in many different parts of plants, including leaves, flowers, shoots, roots, tubers, and seeds [109]. These are complicated compounds with a non-sugar (aglycone) component joined to a sugar moiety. Saponins fall into one of two groups based on their aglycone skeleton. Triterpens saponins, most of which are found in dicotyledonous angiosperms, make up the first class. Steroid saponins, which are primarily found in monotyledonous angiosperms, are found in the second class. Most of the oligosaccharides that make up the glycone portion of saponins are connected to the hydroxyl group by an acetal linkage. Numerous in vivo and in vitro investigations, have shown that plant-derived saponins can increase the immunogenicity of several vaccines. One of the most well-known functions of saponins is their usage as immunoadjuvants, which modulate the immune system produced by cells and aid in creating antibodies [109, 110]. Different saponin chemicals can stop the cell cycle, induce apoptosis and inhibit cancer cells. On rat liver microsomes, Ablise et al. examined the immunotherapeutic effect of glycyrrhizin produced from Glycyrrhiza glabra. With 1.0 mg/mL of glycyrrhizin, the classical complement pathway was significantly inhibited, and the antioxidant activity was increased. Another study by Punturee et al. found that utilising peripheral blood mononuclear cells (PBMCs) to extract Asiaticoside saponin from Centella asiatica had positive results and the data showed that as compared to the non-treated group, asiaticoside administration at 100 mg/kg significantly increased phagocytic index and total WBC count [111]. The immunological responses, both cellular and humoral, are also improved.

2.8 Sterols and sterolins

Combining sterols and sterolins improves NK cells’ capacity to kill the NK 562 target cell line. Additionally, it has been proposed that specific ratios of sterols could restore the delicate balance between Th1 and Th2 cells, which decides how the immune response would turn out. At low concentrations, the phytosterols -Sitosterol and its glycoside more than doubled the in vitro proliferative response of T-cells triggered by sub-optimal amounts of phytohaemagglutinin. Moreover, it has been suggested that sterols and sterolins can control the amounts of Th1 and Th2 mediated cytokines, aiding in enhancing immune responses. Potent immunomodulators, phytosterols, β-Sitosterol, and its glycoside can enhance the proliferative responses of T cells even at low concentrations [112].

Rasool et al. used albino Wistar strain rats to study the immunomodulatory activities of withanolide derived from Withania somnifera. Withanolide administration in the rats dramatically reduced the proliferation of lymphocytes triggered by mitogens, the traditional complement pathway, and hypersensitive reactions. Withanolide might thus be developed into a potent immunosuppressive drug, according to the study [113]. Furthermore, by enhancing the Th1 and Th2 immune responses in mice with disseminated candidiasis, β-sitosterol and daucosterol also demonstrated immunomodulatory action [114]. The immunomodulatory properties of phytosterols isolated from Clinacanthus nutans by employing murine cells were described in another investigation by Lee and colleagues. To evaluate the immunosuppressive effects of phytosterols (stigmasterol, shaftoside, and β-sitosterol), mitogen-induced B and T-cell proliferation and the production of helper T-cell cytokines were observed. The results showed that treatment with phytosterols dramatically reduced T-cell proliferation and enhanced the production of Th1 and Th2 mediated cytokines [115].

The summary of phytocompounds and their mechanism of immunomodulation are expressed in Tables 1–3.

Table 1.

Immunomodulatory actions of flavanoids and coumarins.

Table 2.

Immunomodulatory actions of alkaloids and terpenoids.

Table 3.

Immunomodulatory actions of tannins, glycosides and saponins.

3. Conclusion

Due to their diverse pharmacological properties, active components in medicinal plants have been demonstrated as an essential source of clinical medicines. Traditional medicine uses medicinal plants for health benefits and is thoroughly researched. Any disparity between immune system causes numerous fatal diseases, including cancer, rheumatoid arthritis, and diabetes. According to several recent studies, these disorders can be treated by phytochemicals, present in particular plant species. In vivo, in vitro and ex vivo studies have reported that the administration of phytochemicals such as quercetin, ellagic acid, mangiferin and withanolide, significantly reduced the occurrence of immune-related diseases due to their antioxidant, anti-inflammatory and immunomodulatory activities. Additionally, phytochemicals frequently enhance the Th1 as well as Th2-mediated cytokine production that decreases autoimmune conditions. Despite numerous preclinical and ex vivo studies, other practical proof is needed to support the immunomodulatory action of phytochemicals in preventing and treating immune system-related illnesses. Specific parameter enhancements, like standardised dosage and duration of intervention, are still needed to create the ideal phytochemical immunomodulators.

Acknowledgments

Authors extend a deep sense of gratitude to Hon’ble Vice Chancellor, SRM University, Kattankulathur, Chengalpettu district, Tamil Nadu, India.

Conflict of interest

The authors declare no conflict of interest.