Introduction

Allergic rhinitis (AR), a prevalent chronic inflammatory disease that affects the nasal mucosa of the upper respiratory tract, is categorized into two types: perennial and seasonal. This condition is characterized by recurrent episodes of sneezing, rhinorrhea, nasal congestion, and pruritus. In some patients, it may progress to allergic conjunctivitis, idiopathic dermatitis, allergic pharyngitis or eosinophilic esophagitis.1–3 The rapid advancement of the global economy coupled with accelerated industrialization and continuous changes in climate and environment has led to an increase in allergens and a rise in related risk factors, resulting in higher incidence rates of AR.4 Reports suggest that the global annual cost associated with AR is approximately $20 billion, with prevalence rates ranging from 10% to 40% worldwide and between 20% and 30% among adults; it exceeds 8.5% in school-age children and reaches up to 14% in adolescents in the Americas and Europe.5,6 The World Health Organization Working Group has recognized AR as a global health problem. This increasing prevalence poses a significant challenge to global health, having extensive implications for individuals as well as society at large. Therefore, there is an urgent need to identify safe and effective prevention methods along with control measures.

The pathogenesis of AR remains incompletely understood as it involves a variety of biological pathways primarily associated with regulating the immune system. The entry of allergens disrupts existing immune mechanisms and stimulates allergic reactions that damage the nasal mucosal structure and trigger an inflammatory response.7 Concurrently, it induces abnormal cellular secretion while compromising capillary integrity and impairing circulatory function. These processes can initiate various pathological reactions that may lead to allergic diseases through multiple pathways.8 Furthermore, studies have shown that the immune system transmits inflammatory signals to the central nervous system via both neuro-reflex and non-neuro-reflex mechanisms, activating specific brain regions and altering brain function. This understanding paves the way for targeted pharmacological interventions.9 Currently, in clinical practice, there are 15 commonly utilized antihistamines in Western medicine, including diphenhydramine, levocetirizine, desloratadine, and others; 6 types of glucocorticoids such as budesonide nasal spray, mometasone furoate, and fluticasone propionate; 4 varieties of decongestants including pseudoephedrine, oxymetazoline, and cylozolin; 8 different anti-leukotriene drugs like pranlukast, zafirlukast, and montelukast; along with 3 distinct forms of specific immunotherapy encompassing subcutaneous administration as well as sublingual and nasal immunotherapy.10 Since alternative therapies are excluded from these guidelines, treatment options remain limited. Additionally, other medications with targeted mechanisms are either undergoing clinical trials or have not yet reached the market. To date, many modern therapeutic strategies have failed to intervene effectively in the disease process and merely manage symptoms. As a result, identifying safe and effective drug-targeting pathways and developing multifunctional, multi-targeted drugs for AR within complex biological pathways present both challenges and opportunities.

In recent years, extensive studies have increasingly highlighted the unique therapeutic advantages of natural plant molecules in the treatment of AR. These molecules are characterized by their ability to target multiple pathways and channels while exhibiting minimal side effects, allowing them to influence relevant cells and mediators involved in immune regulation. Notably, the combination of specific monomers and components from Traditional Chinese Medicine (TCM) facilitates the development of personalized and precise therapeutic strategies. The herbs commonly utilized for the treatment of AR encompass Astragalus, Atractylodes macrocephala, Xanthium sibiricum, Divaricate saposhnikovia root, Mentha haplocalyx, Dark plum, and Magnoliae Flos. Their active constituents are frequently observed in curcumin, quercetin, as well as other polyphenols, flavonoids, and saponins.

However, due to the complexity of their pathways and mechanisms of action, the precise role of natural plant molecules in immunomodulation remains ambiguous. This paper aims to comprehensively explore the role of natural plant molecules in immunomodulating AR by systematically addressing the relationship between immunomodulation and the pathogenic aspects of AR, elucidating the specific mechanisms that affect its progression, and detailing the pathways through which natural plant molecules exert their immunomodulatory effects. The findings from this study will help identify new therapeutic targets for combating AR and provide valuable insights for future experimental studies and clinical applications.

Pathogenesis of AR

The pathogenesis of AR, a non-infectious disease, involves the activation of type 2 helper T cells (Th2 cells), which drive the IgE-mediated degranulation of mast cells and subsequent release of inflammatory mediators.11 Dendritic cells and macrophages within the body uptake allergens and inhibit Th1-type cytokine activity through antigenic Th2-type cytokines such as IL-4, IL-5, and IL-13, thereby inducing a series of immune responses. Additionally, cytokines such as IL-2 and INF-γ are involved in further contributing to these immune responses.12 AR progresses through two stages: sensitization and excitation.13 During the sensitization stage, initial exposure to allergens triggers a latency period of 1–2 weeks, during which protease activity compromises the barrier function of nasal mucosa and accelerates the production of pro-inflammatory factors. Concurrently, the nasal mucosal epithelium acts as the primary defense mechanism by extending dendritic cell projections beneath the mucosa upon invasion by allergens. This process exposes antigenic determinants to local lymph nodes, which synergistically stimulate signaling to naïve helper T cells (Th0 cells) and nasal mucosa CD4 cells, leading to their activation as Th2 cells and promoting the secretion of Th2 cytokines. Additionally, this activation results in increased expression of ICAM-1 by vascular endothelial cells. This activation sequence involves eosinophils, mast cells, and cytokines such as IL-4, IL-5, and IL-13. Cytokines play a pivotal role in the subsequent immune response by facilitating the differentiation of B cells into plasma cells and the synthesis of immunoglobulins that convert into specific IgE. This IgE binds to the surfaces of effector cells, such as mast cells and basophils, through the high-affinity receptor FcεRI in a sensitized state. Upon re-exposure to the same allergen, a patient with sensitized AR enters an excitation phase during which the allergen immediately binds to specific IgE, disrupting immune regulation. This phase consists of a rapid-onset and a delayed-onset phase. The rapid-onset phase occurs within seconds to six hours after allergen re-exposure and primarily involve effector cells like mast cells and basophils. During this phase, the allergen bridges two neighboring IgE molecules on effector cell surfaces, prompting cell degranulation and releasing numerous inflammatory mediators, including histamine, leukotrienes, prostaglandins, and platelet-activating factors. These mediators induce clinical symptoms such as nasal itching, sneezing, and a runny nose by binding to various receptors. The delayed phase occurs 12 to 24 hours after re-exposure primarily involving eosinophils as effector cells. Activated eosinophils release inflammatory mediators, including leukotrienes and eosinophil cationic proteins that contribute to symptoms like nasal congestion and a runny nose. During the activation phase, upon re-exposure to the allergen, it immediately binds to specific IgE on the surfaces of mast cells, triggering a pathological immune response (Figure 1).

Figure 1 The pathogenesis of allergic rhinitis is that the allergen enters the nasal cavity. The allergen mainly comes from pollen, mites, animal fur, food and heredity, the mucosal cells produce pathological changes.

Immunomodulatory Structure and Function

The concept of immunity can be categorized into two main types: physiological and pathological types. Animals are capable of distinguishing between two distinct categories of antigens: “self” and “non-self”. The body develops immune tolerance towards self-antigens while mounting rejection responses against non-self antigens. In healthy individuals, physiological immunity effectively detects and responds to pathogenic microorganisms through mechanisms such as phagocytosis, anti-inflammatory actions, and anti-infective responses, thereby maintaining physiological homeostasis.14 However, despite the immune system’s complex structure and numerous components, it can occasionally cause harm by triggering autoimmune diseases, hypersensitivity reactions, and inflammation in response to pathogen invasion. Upon encountering such invasion, the immune system rapidly mobilizes by differentiating immune cells that secrete and release molecules to activate the immune response.15 Subsequently, these immune cells secrete additional molecules that activate other bodily systems in a collaborative effort to eliminate pathogens and restore physiological stability. Modern immunology posits that the immune system of a healthy organism typically maintains stability through self-regulatory mechanisms. Nevertheless, when immune regulation is compromised, this can disrupt physiological balance and lead to disease. In Western medicine, immune-related diseases are addressed by administering exogenous substances to control disease factors, employing various drugs or surgical interventions to modulate the immune response and influence disease progression. Although these interventions often provide rapid relief, they primarily target symptoms rather than addressing the underlying causes of diseases, which may result in relapses and increased difficulty in managing the disease due to developed self-tolerance. As a result, Chinese medicine has gained attention from immunologists for its distinctive diagnostic and treatment approaches (Figure 2).

Figure 2 The Allergen invades the nasal mucosa, first into the neutrophil, triggering an oxidative stress response. It affects TSLP and releases Ilc-2. Ilc-2 release IL-5 factor under the activation of Allergen, make it act on B cells, and form memory B cells under the influence of IL-6, igE production and IL-1 cytokine production affect Th17 cell secretion. TSLP leads to imbalance of Th1, Th2, Treg and Th17 cells in T cells, and stimulates dendritic cell. Th2-releasing factors and IgE receptors act on macrophages to release IgE and other factors, il-33 and IL-4 factors released by Th2 Act together with IL-5 factors released by Ilc-2 on eosinophil granulocyte. The Eosinophil granulocyte release ECP, MBP and IgE receptors, which act on mast cells and basophil granulocyte. The mast cells degranulate to release calcium and histamine, and the basophil granulocyte degranulate to release histamine, which reacts with the nasal mucosa, initiate the corresponding inflammatory response.

Granulocytes Neutrophil

After differentiating and maturing in the bone marrow, neutrophils are released into either peripheral blood or tissues. In these locations, they carry out phagocytosis and degranulation functions that serve as the first line of innate immune defense.16 Stimulation by allergens on nasal mucosa results in a significant increase in mucosal neutrophils count along with T cells activation and enhanced migratory capacity for eosinophils.17 During the initial phase of AR, neutrophils, which are recruited prior to eosinophils, induce Th2-type inflammation in the airways through the formation of neutrophil extracellular traps (NETs), releasing inflammatory mediators.18 As AR progresses, the response to allergens is characterized by increased neutrophil chemotaxis, phagocytosis, and reactive oxygen species (ROS) production that contribute to oxidative stress. Furthermore, eosinophil cationic proteins (ECPs) are produced via an IgE-dependent mechanism, which further activates eosinophils and exacerbates inflammation.19

Basophil Granulocytes

Basophils, which mature in the bone marrow and are released into the peripheral blood, constitute only 0.5–1.0% of leukocytes.20 Despite their limited abundance, they rapidly synthesize Th2-type cytokines, thereby effectively supporting the immune response in AR.21 Basophils share several characteristics with mast cells and function as both Th2-inducing cells and antigen-presenting cells (APCs), primarily through the expression and engagement of the IgE receptor FcεRI on their cell surfaces.22 Upon exposure to allergens, allergen-specific IgE binds to basophils and cross-links with them, triggering the release of effector molecules such as histamine and leukotrienes. Notably, basophil activation is initiated by FcεRIα-mediated cross-linking via IgE antibodies independent of their presence on the basophil membrane. Basophils play a crucial role in the onset, development, and maintenance of AR as major effector cells that are highly sensitive to IgE-mediated activation.23 Research has demonstrated that basophils contribute to the pathogenesis of various allergic diseases, including AR. Clinically, the basophil activation test (BAT) aids in diagnosing AR and monitoring patient responses to therapy.24 However, the role of basophils in AR remains controversial, and further research is required to elucidate and clarify their involvement in the development and onset of AR.

Eosinophils

Eosinophils (EOS), derived from bone marrow hematopoietic stem cells, undergo differentiation and maturation within the bone marrow prior to being released into the peripheral blood.25 The development of EOS is influenced by various cytokines, including IL-5, IL-33, and granulocyte-macrophage colony-stimulating factor (GM-CSF).26 EOS serve as effector cells in natural immunity, along with neutrophils, participate in antibody-dependent cell-mediated cytotoxicity, resulting in tissue damage and inflammation. In allergic diseases, EOS go through multiple stages of development, adhesion, migration, and activation before being recruited to the site of inflammation.27 Mature EOS, regulated by IL-5, migrate from the bone marrow into the bloodstream. Following allergen stimulation, mast cells and endothelial cells at the site of inflammation secrete various cytokines that activate surface integrins (such as β1, β2, and β7) on EOS, thereby promoting their aggregation at the site. Once EOS adhere to epithelial cell ligands via integrins, a signaling cascade is activated, leading to the release of cytotoxic particles specific to EOS as they migrate toward the inflammation site, guided by the synergistic effects of chemokines.28 Additionally, activation products of eosinophils, including ECP and major basic protein (MBP), stimulate mast cells and basophils to release histamine, which increases vascular permeability and mucus secretion.29,30 This process ultimately damages the epithelium of respiratory mucosa and exacerbates local inflammatory responses.

Macrophages

Macrophages function as pivotal bridge cells between innate and adaptive immunity, playing a crucial role in coordinating immune responses. Upon pathogen invasion, macrophages present in the blood or tissues phagocytose and eliminate pathogens, induce cellular immune responses, and facilitate tissue repair and remodeling.31 Additionally, due to their inherent plasticity, macrophages exposed to diverse microenvironmental stimuli can differentiate into various subpopulations, predominantly M1 and M2-type macrophages.32 The roles of macrophages include: 1) providing antigenic information to lymphocytes; 2) producing oxygen free radicals and lymphokines, such as IL-1, which modulate inflammatory responses; 3) generating inflammatory mediators like arachidonic acid and platelet-activating factor; 4) modulating lymphocyte activation; and 5) exhibiting limited affinity for the IgE Fcε surface receptor. Macrophages play a crucial role in balancing Th1/Th2-type immune responses in AR.33 Cytokines and chemokines secreted by M2-type macrophages facilitate the differentiation of Th2 cells and the recruitment of EOS. Th2-type cytokines, such as IL-4 and IL-13, promote macrophage polarization towards the M2 phenotype through STAT6 activation. Conversely, M2 macrophages secrete various cytokines and chemokines including Arginase-1 (Arg-1), CCL17, and CCL24 to regulate eosinophil recruitment and mediate allergic inflammation.34 Furthermore, increased TGM2 expression in M2 macrophages enhances eosinophilic infiltration. Additionally, macrophages and classic T-lymphocyte immune mechanisms complement each other and regulate the progression and resolution of allergic diseases while also influencing the course of AR.35,36

Mast Cells

Mast cells (MCs) are the primary effector cells in type I hypersensitivity reactions, playing a crucial role in the activation and aggregation of neutrophils and EOS. Originating from the bone marrow, MCs circulate in the bloodstream in an immature form before migrating to various tissues.37 The degranulation of MCs is central to the pathophysiology of AR, with the secretory response varying significantly based on the size and distribution of FcεRI clusters.38 Immature MCs undergo maturation through IgE-induced histamine synthesis and cytokine release. Upon maturation, they produce and store numerous dense cytoplasmic granules, which are released in response to specific stimuli.39 The most common stimulus for this release is cross-linking of IgE molecules via multivalent antigen binding to the high-affinity IgE receptor, FcεRI. The binding of IgE to multiple FcεRI on the cell membrane initiates the phosphorylation of downstream proteins, activating signaling molecules and generating second messengers.40,41 This cascade results in the release of Ca2+ from the MC’s endoplasmic reticulum, leading to subsequent MC degranulation. Degranulation through the IgE-dependent pathway results in various symptoms, including damage to epithelial tissue, thickening of the basement membrane, hypertrophy of airway smooth muscles, and increased respiratory mucus.42,43

Dendritic Cells (DCs)

Dendritic cells (DCs) are derived from hematopoietic stem cells in the bone marrow. In the human nasal mucosa, DCs predominantly reside in the epithelium and lamina propria. They traverse the tightly connected epithelium through dendritic projections.44 Based on their origin, DCs can be classified into plasma cell-like dendritic cells (pDCs) and myeloid dendritic cells (mDCs).45 The two principal types of DCs found in blood and lymphoid tissues are conventional DCs (cDCs) and pDCs. Functioning as “transmitters” in the pathogenesis of AR, DCs by capture and present allergens to naive T cells, subsequently initiating a cascade of immune responses.46–48 Together with macrophages and B cells, DCs form the three primary populations of APCs. Unlike macrophages, which do not migrate to lymph nodes or activate T cells ex vivo, DCs possess the ability to transport antigens to draining lymph nodes, thereby initiating T cell activation. Only live, mature, and fully functional DCs that migrate to the lymph nodes can effectively stimulate a T cell response.49,50

B-Cells

B cells, which are essential for humoral immune defense and effective antigenic recognition, migrate back to local lymph nodes and serve as sources of allergen-specific IgE in AR.51 They can either mediate an immediate immune response by producing IgG or act as regulatory B cells in the absence of pathogenic entities.52 AR is categorized into two phases: sensitization and stimulation. During the sensitization phase, the initial exposure of the nasal mucosa to allergens involves a latency period of 1–2 weeks. During this time, protease activity impairs the barrier function of the nasal mucosa upon contact with the allergen and accelerates the production of pro-inflammatory factors. Patients with AR exhibit a significant increase in memory B cells, plasma cells, and CD19+CD24hiCD27+ Bregs, while naïve B cells are substantially reduced compared to healthy individuals.53 The initial increase in serum allergen-specific IgE characterizes the B cell response, likely representing a memory response triggered by exposure to allergens. Memory B cells, which become activated upon encountering antigens, maintain long-term sensitization or tolerance to allergens through rapid proliferation, somatic mutations, and class-switch recombination.54 Treg cells inhibit the functions of B cells and influence their proliferation, activation, and apoptosis. In AR patients, B cells have a notable impact on the magnitude, duration, and affinity of IgE production. The IL-21 receptor signaling in B cells is crucial for regulating IgE.55

T-Cells

T lymphocytes, crucial regulators of the cellular immune response, mature into two primary types: CD4+ T cells and CD8+ T cells. CD4+ T cells can be further subdivided into three subtypes based on their secretion of cytokines: Th0, Th1, and Th2.56 Th1 cells secrete cytokines such as IL-2, IL-12, and INF-γ that play a role in in humoral immunity and regulate the differentiation of cytotoxic T helper cells, thereby contributing to the pathogenesis of AR. In contrast, Th2 cells produce cytokines like IL-4 and IL-5, which activate MCs, EOS, and basophils. These immune cells accumulate at sites of inflammation where they degranulate and release inflammatory mediators to modulate AR.57 Regulatory T cells (Tregs), a specialized subtype of T lymphocytes characterized by the expression of CD4+, CD25+, and the transcription factor Foxp3, possess immunoregulatory functions exerting suppressive effects on immune responses. Thymic Treg cells (tTregs) interact with DCs to promote immune tolerance. Tregs can be categorized into two groups based on their origin: tTregs and induced Treg cells (iTregs), each playing distinct roles in immune regulation.58 In vivo, Tregs either differentiate directly in the thymus or develop from conventional CD4+ T cells in the periphery. Foxp3, a crucial regulator of Treg development and function, is essential for inducing and maintaining the Treg cell phenotype. Foxp3+ Treg cells sustain their suppressive functions both in vivo and in vitro after expansion, presenting potential therapeutic avenues for AR.59 The acetylation, phosphorylation, and ubiquitination of Foxp3 are integral to the development and functional maintenance of tTreg cells by influencing protein stability and DNA-binding capacity. Foxp3 collaborates with other transcription factors and proteins to shape the transcriptional profile and effector functions of Treg cells. Disrupting specific protein interactions with Foxp3 diminishes Treg cell functionality. Under specific environmental conditions, Treg cells can modulate the components of the Foxp3 protein complex to regulate inflammation associated with AR.60 The expression and stability of Foxp3 are crucial in maintaining the functionality of Treg cells. Treg cells exhibit both plasticity and instability, as activated Tregs can inhibit the interaction between T-cell responses and DCs. Post-translational modifications, including hyperacetylation, play a crucial role in regulating the plasticity and stability of Treg cells by modifying Foxp3. IL-2, a key cytokine for promoting T cell proliferation and differentiation, plays an indispensable role in the development, survival, and function of Foxp3+ Treg cells. Studies have demonstrated that naturally occurring Treg cells are characterized by their expression of Foxp3. The suppressive function of Treg cells is influenced not only by their expression of Foxp3 but also by the microenvironment. Tregs exert immunosuppressive effects through cell-contact mechanisms and secretion of inhibitory cytokines, while also influencing T cell function by regulating APCs.61 Foxp3 is currently recognized as the most reliable molecular marker for natural Treg cells, elucidating the mechanisms underlying Treg cell differentiation. Foxp3 collaborates with various transcription factors and proteins to shape the transcriptional profile and effector functions of regulatory T (Treg) cells.62 Disruption of specific protein interactions with Foxp3 impairs the functionality of Treg cells. Under certain environmental conditions, Treg cells can modulate the components of the Foxp3 protein complex to regulate inflammation associated with AR. The expression and stability of Foxp3 are crucial for maintaining Treg cell functionality. Treg cells exhibit both plasticity and instability; activated Tregs can inhibit the interaction between T-cell responses and DCs.63–65 Post-translational modifications of Foxp3, including hyperacetylation, play significant roles in regulating the plasticity and stability of Treg cells. Interleukin-2 (IL-2), a key cytokine for T-cell proliferation and differentiation, is indispensable for the development, survival, and function of Foxp3+ Treg cells. Numerous studies have demonstrated that naturally occurring Treg cells are characterized by the expression of Foxp3.66 The suppressive function of Treg cells is not only influenced by Foxp3 expression but also by the surrounding microenvironment. In addition to regulating APCs, Tregs exert their immune-suppressive effects through both cell-contact mechanisms and secretion of inhibitory cytokines. Currently recognized as the most reliable molecular marker for natural Treg cells, Foxp3 elucidates the underlying mechanisms involved in Treg cell differentiation.67 However, the instability in Foxp3 expression can significantly diminish their suppressive capacity, potentially disrupting immune tolerance and contributing to AR. The mechanisms governing Foxp3 stability and Treg cell integrity remain incompletely understood.68 Furthermore, understanding these regulatory mechanisms is crucial due to the impact of specific Treg cell populations on the severity of AR when exposed to allergens. Clinical trials have investigated the therapeutic potential of Treg cells for immune disorders, suggesting their prospective application in managing AR.69,70

Inflammatory Factor IL-1

Interleukin-1 (IL-1), a lymphocyte-stimulating factor commonly found in the forms of IL-1α and IL-1β, is predominantly produced by macrophages.71 Additionally, almost all nucleated cells, including B cells and DCs, can produce IL-1. IL-1 plays a role in negative regulation of the inflammatory signaling pathway mediated by the IL-1 receptor/Toll-like receptor.72 Research indicates that IL-1R8 significantly negatively regulates Th17 cell differentiation, proliferation, and function by directly inhibiting the IL-1 signaling pathway.73 Immunomodulatory effects of IL-1 include: 1) synergistic effects with antigens to activate CD4+ T cells; 2) promotion of B cell growth and differentiation, enhancing CD4+ T cell activation and expression of the IL-2 receptor, leading to a 100-fold increase in the number of hemolytic vacuoles in splenocytes (PFC), indicating the role of IL-1 in promoting antibody production; 3) enhancement of antigen-presenting capacity for monocytes, macrophages, and other APCs; 4) synergy with IL-2 or interferon to enhance NK cell activity; and 5) attracting neutrophils, which subsequently release inflammatory mediators.74–76

IL-2

Interleukin-2 (IL-2), a cytokine produced by activated Th1 cells, primarily promotes the proliferation of killer T cells and NK cells, enhances the differentiation and proliferation of B cells, stimulates antibody production, and induces lymphokine-activated killer cells.77 IL-2 is crucial for the immune response; nonetheless, aging and various diseases can diminish IL-2 production, subsequently impacting the entire immune system. In order for IL-2 to exert its immunomodulatory effects, it must bind to the activated membrane interleukin-2 receptor (mIL-2R).78 The soluble interleukin-2 receptor (sIL-2R), a polypeptide released into the bloodstream by activated Th1 cells, competes with mIL-2R for IL-2 binding and inhibits the clonal expansion of activated T cells. The IL-2/IL-2R system plays a central role in regulating the body’s immune response.79

IL-3

Interleukin-3 (IL-3), an important member of the interleukin family and also referred to as multi-directional colony-stimulating factor (multi-CSF), is a cytokine produced by T lymphocytes.80 It stimulates the proliferation in the immune response-associated cells, including Th2 cells that secrete pivotal cytokines. IL-3 is crucial in the pathogenesis of AR as it stimulates the proliferation and differentiation of multipotent hematopoietic stem cells, MCs, EOS, and basophils.81,82 Furthermore, IL-3 induces not only multipotent hematopoietic stem cell and MCs proliferation and differentiation but also that of EOS and basophils.83 Due to its broad impact on various cell types, IL-3 is also referred to as a multi-colony stimulating factor. Under normal circumstances, IL-3 concentration is tightly regulated through negative feedback. However, in allergic conditions, activation of the IL-3 gene leads to abnormally high concentrations of this cytokine.84

IL-4

Interleukin-4 (IL-4) is a cytokine secreted by type II helper T cells (Th2 cells). As a hallmark of Th2 cells, IL-4 promotes the proliferation of activated B and T cells and facilitates the differentiation of CD4+ T cells into type II helper T cells.85 Additionally, it regulates humoral and adaptive immunity, induces class switching to IgE in B cell antibody production, and upregulates the expression of type II major histocompatibility complex.86 IL-4 plays critical roles in metabolic responses such as promoting the differentiation of type 2 helper T lymphocytes, inducing IgE production, upregulating cellular adhesion molecule 1 expression via the IgE receptor, facilitating eosinophil migration to the lungs, inhibiting apoptosis in T lymphocytes and promoting mucus hypersecretion.87 Furthermore, IL-4 enhances the adhesion of EOS and basophils to endothelial cells and inhibits the production of γ-interferon.88 Additionally, IL-4 prompts the proliferation, differentiation, and maturation of MCs. Upon activation, MCs release IL-4 into the extracellular microenvironment, which in turn activates T cells to produce more IL-4 and further initiates recruitment of inflammatory cells.89 The documented impact of IL-4 on MC proliferation, differentiation, and maturation is well-established. Moreover, it has been shown that IL-4 inhibits TGF-β-mediated FoxP3 expression, thereby preventing the conversion of naive T cells into Tregs. Allergenic individuals exhibit increased secretion of IL-4 following allergenic stimulation.90,91

IL-5

The multifunctional cytokine Interleukin-5 (IL-5) is produced by cells of the immune system. It is primarily produced by activated T cells and is particularly abundant in the Th2 cell subpopulation.92 IL-5, secreted by activated Th2 helper cells, possesses proliferative, chemotactic, and activating functions for EOS.93 When EOS infiltrate the nasal mucosa, they can release ECP and MBP, both of which are cytotoxic and neurotoxic.94 These proteins can damage the nasal mucosa and enhance glandular secretion, leading to symptoms such as nasal congestion, itching, runny nose, and sneezing. IL-5 stimulates the proliferation and differentiation of B cells while also promoting antibody production to enhance the humoral immune response. On one hand, IL-5’s activation of EOS synergizes with other cytokines to enhance their inflammatory infiltration and increase the expression of adhesion molecules.95 On the other hand, IL-5 prolongs the lifespan of EOS and alters their density from normal to low. While IL-5 activates EOS, these cells can also produce more IL-5 themselves, creating a feedback loop that exacerbates and prolongs AR.96,97

IL-6

Interleukin-6 (IL-6), a cytokine secreted by Th2 cells, is also produced by MCs, epithelial cells, and endothelial cells within the body. IL-6 exerts regulatory effects on the growth and differentiation of various cell types.98 The cytokine induces T-cell activation, growth, and differentiation, as well as promoting the differentiation of Th0 cells into Th17 cells and MC proliferation.99,100 In response to IL-6 stimulation, B-cells differentiate into mature plasma cells that subsequently secrete IgE. IL-6 plays a crucial role in the cascade of inflammatory mediators contributing to fibrosis and airway remodeling. The effects of IL-6 are dose-dependent: normal levels have beneficial effects, while excessive production leads to various inflammatory damages. Serum levels of IL-6 increase under conditions such as inflammation, infection, and certain tumors.101

IL-9

Interleukin-9 (IL-9), produced by Th2 cells, serves as an important factor in immune regulation and the inflammatory response.102 By enhancing MC survival and function, IL-9 promotes inflammation and triggers the release of additional inflammatory mediators. IL-9 acts on effector Th2 cells and memory T cells of the Th2 phenotype, which directly differentiate from them.103 In IL-9 cells, the transcription factor PU.1 activates Th9 cell differentiation while inhibiting Th2 cell differentiation. As a result, cytokine expression in Th2 cells is significantly reduced, whereas IL-9 expression is markedly increased.104,105

IL-10

Interleukin-10 (IL-10), derived from multiple cell types, is a multifunctional cytokine that regulates cellular growth and differentiation and plays a crucial role in inflammatory and immune responses.106 IL-10 exerts its influence on key functions of monocyte macrophages, including the release of immune mediators and antigen presentation. In brief, IL-10 inhibits the ability of monocyte macrophages to promote natural and specific immunity functions while enhancing cytostatic, immune tolerance-inducing, and scavenging activities.107 Indeed, IL-10 suppresses the secretion of inflammatory mediators by monocyte macrophages, thereby reducing the levels of TNF-α, IL-1β, IL-6, IL-8, G-CSF, and GM-CSF in response to LPS and IFN-γ.108 Furthermore, IL-10 promotes the release of anti-inflammatory factors, including IL-1 receptor antagonists and soluble TNF-α receptors. Thus, IL-10 significantly reduces the levels of key cytokines involved in innate immunity and inhibits antigen presentation by monocyte macrophages.109 Moreover, IL-10 suppresses the synthesis of IL-12, thereby hindering the Th1 immune response. The inhibitory effect of IL-10 on cellular factor production and antigen presentation is further enhanced by CD4+ T cell suppression. Additionally, IL-10 hampers IFN-γ production by Th1 cells, while a deficiency in IFN-γ enhances APC inactivation. IL-10 also decreases macrophage secretion of essential cytokine IL-23 required for Th17 cell-mediated immunity.110

IL-12

Interleukin-12 (IL-12), produced mainly by activated macrophages and DCs, is a significant immunomodulatory cytokine.111 This cytokine is crucial in promoting the secretion of Th1 cytokines, such as IFN-γ, which enhance immune responses of Th cells. Simultaneously, it inhibits the production of Th2 cytokines, like IL-4, that suppress immune responses of Th2 cells.112

IL-13

Interleukin-13 (IL-13), an immunomodulatory protein with inhibitory properties, shares both functional and structural similarities with IL-4. It is primarily produced by Th2 cells and MCs. As members of the Th2 gene family, they both utilize the same receptor chain and signaling system. In the absence of IL-4, IL-13 serves as a critical factor in inducing Th2 responses and is a major mediator of Th2 cell production.113 During the development of allergic diseases, such as AR, levels of IL-13 are significantly elevated. IL-13 induces mitosis in B-lymphocytes activated by IgM or anti-CD40 monoclonal antibody, contributing to their differentiation and antibody class switching. Additionally, it enhances the production of IgE, IgM, and IgG, while inhibiting apoptosis in B-cells.114 In the presence of activated CD4+ T cells or anti-CD40 monoclonal antibody, IL-13 autonomously induces B cells to synthesize IgE. IL-13 functions as a TH2 cell effector by inducing the synthesis and extracellular secretion of IgE by activated B lymphocytes. Additionally, it enhances the body’s response to mutagens, promotes cuprocyte proliferation and gland secretion, and exacerbates nasal cicatrization in AR.115,116 As a TH2 effector, IL-13 plays a pivotal role in the pathogenesis of AR through its regulation of Th1 and Th2 cell functions, promotion of IgE secretion by B cells, and localization of the response to mutagens.117

IL-17

Interleukin-17 (IL-17), a subset of pro-inflammatory cytokines, is mainly synthesized by activated CD4+ lymphocytes and stimulates T lymphocytes, particularly during the initial stages of inflammation, affecting a variety of cells and tissues.118 It induces mesenchymal stromal cells to secrete inflammatory and hematopoietic cytokines, such as IL-6 and IL-8. Furthermore, it prompts fibroblasts to facilitate the proliferation and differentiation of CD34+ hematopoietic progenitors, a process closely related to autoimmunity and tumorigenesis.119 Additionally, IL-17 amplifies inflammation by inducing the release of neutrophil chemokines.120

IL-18

Interleukin-18 (IL-18), a member of the serum IL-1 family, is a widely distributed pro-inflammatory factor with diverse biological activities. It is expressed in various cells including B-cells, T-cells, macrophages, osteoblasts, and keratinocytes.121 In AR patients, IL-18 can up-regulate IgE production and activate Th2 cells to produce cytokines. It synergizes with IL-12 to produce IFN-γ, which inhibits IL-4-induced IgE synthesis. This ultimately reduces serum IgE levels, decreased eosinophil aggregation in the nasal mucosa, and suppressed proliferation of Th2 cells. These actions result in decreased release of inflammatory mediators and airway hyperresponsiveness (AHR), ultimately reducing airway inflammation.122,123 Simultaneously, IL-18 promotes the secretion of IL-4 and IL-13 from T cells, MCs, and basophils, playing a dual regulatory role in Th1 and Th2 cytokine production as well as IgE synthesis. Furthermore, IL-18 enhances IFN-γ production through synergistic and autocrine effects during AR progression, inhibiting the synthesis of IgE induced by IL-4 while promoting Th1 differentiation and suppressing Th2 cells to affect the immune balance between Th1/Th2.124,125 It also activates Th2 cells to produce cytokines, contributing to the immune imbalance between Th1/Th2 associated with AR.126

IL-22

Interleukin-22 (IL-22), a member of the IL-10 cytokine family, is primarily synthesized by various immune cells, including Th17 and Th22 cells. IL-22 is crucial in maintaining the barrier function of the respiratory mucosa by promoting epithelial cell survival and repair, thereby enhancing resistance to mechanical and chemical damage.127 In AR, this function helps mitigate mucosal damage and strengthens defenses against external allergens.128 It collaborates with cytokines like IL-17 and may also be implicated in releasing inflammatory mediators that exacerbate the nasal mucosa’s inflammatory response, characterized by mucosal swelling and increased secretions.129

IL-33

The cytokine Interleukin-33 (IL-33), recently identified as tissue-derived, connects natural and adaptive immunity and promotes mucosal Th2 inflammatory responses; it is also referred to as an epithelial-derived alerting hormone. The ST2 receptor, specific to IL-33, becomes activated when IL-33 binds to ST2 on the surfaces of MCs, various immune cells (including Th2 and ILC2s), and DCs.130 This interaction recruits downstream signaling molecules that activate nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK), which mediate the release of inflammatory mediators from Th2 cytokines and promote allergic diseases.131 The ST2 receptor is prevalent among a variety of immune cells, including Th2 cells. Binding of IL-33 to the ST2 receptor forms an immune complex expressed in Th2 cells, promoting the release of inflammatory mediators such as IL-4, IL-5, and IL-13 while regulating the functions of basophils, MCs, EOS, and intrinsic lymphocytes.132

IFN-γ

Interferon-γ (IFN-γ), a characteristic cytokine secreted by Th1 cells, activates macrophages and neutrophils, inhibits the differentiation of Th0 cells into Th2 cells, and suppresses secretion, proliferation, and activation of Th2 cells. Consequently, it indirectly hampers type I allergic reactions.133 Inherently inflammatory in nature, Th1 cells can elicit an associated inflammatory response when allergen-specific Th1 cells are transferred to a patient’s lungs. Although this transfer does not directly induce AHR that exacerbates asthma and allergic reactions, IFN-γ is frequently detected at sites of allergic inflammation where it promotes inflammatory responses.134 Additionally, IFN-γ induces inducible nitric oxide synthase (iNOS) production in macrophages and promotes NO synthesis. It also stimulates microglial astrocytes to produce iNOS, potentially contributing to the development of certain allergic diseases.

TNF-α

Tumor necrosis factor-α (TNF-α), primarily produced by macrophages and monocytes, plays a crucial role in the pathogenesis of allergic diseases.135 In patients with AR, the nasal mucosa exhibits high levels of macrophages, monocytes, polymorphonuclear leukocytes, and MCs, all secreting TNF; consequently, elevated TNF concentrations are observed in their serum.136 TNF-α is produced and released by IgE-dependent activation of monocyte-macrophages, inducing the expression of adhesion molecules in epithelial cells. This cytokine also promotes the infiltration and activation of inflammatory cells, stimulates monocytes and T-cells to secrete IL-6 and IL-8, and directs Th cell differentiation towards Th2 phenotype. This cascade leads to an IgE-mediated type I hypersensitivity reaction, causing immune damage.137,138

TGF-β

Transforming growth factor-β (TGF-β) belongs to a superfamily that regulates cellular growth, differentiation, and metabolism. Secreted by various cells, TGF-β primarily governs the healing process of injuries and influences cell proliferation, differentiation, immune responses, and fibrosis.139 In terms of immune regulation, TGF-β1 has been discovered to chemotactically attract and regulate neutrophils, EOS, monocytes, and other inflammatory cells. This prompts their accumulation at the site of inflammation and triggers an inflammatory response.140 Additionally, TGF-β1 inhibits the differentiation of CD4+CD25− T cells into Treg cells while promoting a bias towards Th17 cell differentiation.141 These highly effective pro-inflammatory effectors enhance the recruitment of inflammatory cells through the release of mediators, thereby expanding and sustaining acute inflammatory responses in the body. Concerning immunosuppression mechanisms, TGF-β1 inhibits the maturation and differentiation processes in immune cells such as Th1 cells, Th2 cells, B cells, as well as innate lymphocytes, while reducing associated cytokine releases like IFN-γ and IL-2.142 The involvement of TGF-β1 further enhances the expression in the nasal mucosa, induces histopathological changes, and potentially leads to tissue remodeling within the nasal mucosa.143

T-Cell Levels

During the immune response, CD4+ T helper (Th) cells undergo several stages of differentiation. Initially, upon stimulation by external antigens and under the influence of various inducing factors, CD4+ T cells can differentiate into diverse subpopulations, including Th1, Th2, Th17, Th9, and Tregs. This process of differentiation is guided by the cytokines produced and the physiological functions of these cells. While operating independently as distinct T cell subpopulations, they also demonstrate interconnections.

Th1/Th2

When allergens invade the body, APCs process and present allergenic peptides to Th0 cells, initiating their differentiation into Th2 cells and resulting in a Th1/Th2 immune imbalance.144 Th2 cells facilitate the synthesis and secretion of IgE by MCs and promote IgE release from B cells through various cytokines. Concurrently, Th2 cells secrete cytokines such as IL-4 and IL-13, with IL-4 playing a crucial role in driving further differentiation from Th0 to Th2 and directly stimulating B cell production of IgE antibodies.145 In contrast, Th1 cells secrete IL-2 and interferon-γ (IFN-γ), both of which inhibit in vivo IgE production by blocking IL-4-induced IgE synthesis.146 In patients with AR, IgE binds to the IgE-FcεRI receptor on MCs, macrophages, and epithelial cells’ surfaces, sensitizing these cells. Upon re-exposure to the allergen, it crosslinks two adjacent surface-bound IgEs, triggering the release of inflammatory mediators, cytokines, and neuropeptides that affect the nasal mucosa, leading to various clinical symptoms of AR.147

Treg/Th17

Under normal physiological conditions, there is a dynamic equilibrium between the number and function of Th17 and Treg cells. Disruption of this balance can lead to the onset and exacerbation of various diseases, typically characterized by an increase in Th17 cells and a decrease in Treg cells. Th17 cells primarily contribute to tissue damage and inflammatory cell infiltration through secretion of IL-17, which induces the expression of metalloproteinases, chemokines, and pro-inflammatory cytokines.148 Treg cells, as a subset of T cells, inhibit and regulate the proliferation and activation of T lymphocytes, thereby exhibiting anti-inflammatory activity and maintaining immunological homeostasis. It is worth noting that a reduction in Treg cells is associated with several autoimmune diseases. In AR patients, Th17 cells exhibit enhanced pro-inflammatory effects compared to healthy individuals, resulting in elevated levels of cytokines such as IL-17, IL-25 (also known as IL-17E), and TNF-α.149 Additionally, Th17 cells stimulate other cell types to produce significant amounts of inflammatory cytokines, including IL-6, IL-8, and GM-CSF. Collectively, these cytokines exacerbate the inflammatory response, further worsening the clinical symptoms observed in AR.150

Natural Plant Molecules Modulate Pathways Associated With AR Immunomodulation

This paper initially discusses recent advancements in the immunomodulatory mechanisms associated with AR. Subsequently, we summarize and analyze experimental studies, recent reviews, and web-based pharmacological analyses pertaining to the utilization of natural plant molecules for AR treatment. We also provide a summary of the effectiveness and corresponding pathways by which these plant compounds modulate immunomodulation. The chemical structures of these plant compounds are shown in Figure 3.

Figure 3 Continued.

Figure 3 Chemical structure of natural plant molecules.

Polyphenols (Table 1) Curcumin

Curcumin (Cur), the primary active compound found in turmeric, is a natural polyphenol with a medicinal history spanning over 4000 years. It is derived from the Curcuma longa plant and has been widely utilized in traditional Chinese medicine. In the past decade, there has been a surge in research focusing on the pharmacological activities and mechanisms of action of curcumin, attracting growing attention from the scientific community.162,163 Numerous studies have confirmed that curcumin possesses diverse properties, including anti-inflammatory, antioxidant, antibacterial, antifungal, antiprotozoal, antiviral, hepatic and renal protective, anti-fibrotic, anticancer, and anti-carcinogenic effects. Additionally, it exhibits anti-fibrotic and anticancer effects without causing significant toxic side effects.164,165 Recent findings suggest that curcumin can inhibit histamine release in animal models of type I and type IV allergic reactions, highlighting its potential as an anti-allergic agent. In a study conducted by Zhang Ning et al,151 curcumin was administered to OVA-sensitized mice, resulting in a reduction of immune cytokine levels through the inhibition of histamine release and specific IgE production in MCs. Furthermore, curcumin demonstrated its efficacy in alleviating nasal symptoms and improving the morphology of damaged nasal mucosa by attenuating histamine and specific IgE levels, reducing TNF-α expression, and inhibiting the release of inflammatory mediators through the stabilization of I-κBα in the cytosol, thus preventing PM-stimulated nuclear translocation of NF-κB in MCs. Under physiological conditions, the human body maintains redox homeostasis. Nevertheless, disruption of this balance caused by internal or external factors that increase free radical concentrations can lead to oxidative damage to biological macromolecules and various diseases.166 Furthermore, a study on human nasal fibroblasts demonstrated that curcumin reduced the levels of ROS induced by urban particulate matter (UPM), achieving this through the activation of the Nrf2/HO-1 pathway.152 It was observed that curcumin activated Nrf2 and inhibited extracellular signal-regulated kinase (ERK) in UPM-exposed fibroblasts, significantly increasing antioxidant enzymes like heme oxygenase-1 (HO-1) and superoxide dismutase (SOD2). Consequently, this alleviated oxidative stress and mitigated allergic nasal symptoms.

Table 1 The Immunomodulatory Effects and Mechanisms of Natural Plant Polyphenols on AR Were Summarized

Resveratrol

Resveratrol is a naturally occurring polyphenol found in various herbs and foods, including tiger nuts, grapes, and soybeans. Currently, it is marketed as both a nutritional supplement and food additive. Due to its broad pharmacological effects, resveratrol exhibits potent properties in terms of anti-inflammatory, antioxidant, antiviral, hypolipidemic, hypoglycemic, and anticancer activities.167,168 It is anticipated to emerge as a novel therapeutic agent for disease prevention and treatment. Experiments conducted on different animal models have confirmed that resveratrol can repair damaged nasal mucosa cells by regulating the release of inflammatory factors and alleviating allergy symptoms through the reduction of oxidative stress.160,169 In a randomized controlled trial focusing on AR, it was demonstrated that resveratrol has the ability to regulate serum levels of inflammatory factors and T-lymphocyte subpopulations.170 This study further revealed that modifying the stoichiometry of resveratrol resulted in reduced infiltration of inflammatory cells,153 decreased serum levels of Th2 cytokines IL-4, IL-13, and OVA-sIgE; inhibited polarization of Th2 cells; regulated immune function; and altered Th2 polarization, while modifying the inflammatory response. Resveratrol not only suppresses the elevation of peripheral blood INF-γ but also mitigates histopathological changes in the nasal turbinate mucosa.154 It reduces eosinophil infiltration and inhibits glandular secretion. Additionally, resveratrol was found to decrease SOD activity by inhibiting the TXNIP-oxidative stress pathway,155 subsequently reducing MDA and ROS production. As a result, this led to the down-regulation of inflammatory mediators in splenic mononuclear cells and decreased levels of PGD2, LTC4, ECP, IL-4, IL-5, IL-6, IL-33, and TNF-α. However, further large-scale animal and human studies are necessary to elucidate and refine the mechanisms of action of resveratrol for potential therapeutic enhancement.

Gallic Acid

Gallic acid (GA) is a key constituent of several traditional Chinese herbal plants, including Pentaphyllum, Pawpaw Rhubarb, Cornu Cervi, and Myrtus communis. Previous studies have demonstrated that GA exhibits a range of properties, including antioxidant, anti-inflammatory, anti-allergic, antibacterial, antiviral, and antitumor effects with minimal toxicity to normal cells.171,172 These findings suggest the significant potential of GA in the field of medicine.173 Recently, Shenna et al conducted an experimental study on the effects of GA in mice with AR.156 The results revealed that GA modulates the Nrf2/NF-κB pathway which influences immunoglobulin levels (IgE, IgG1, and IgG2a), as well as alters nasal mucosa thickness. These outcomes indicate that GA can enhance immune function and augment resistance against pathogens in nasal mucosa while also modulating inflammatory responses. Sang-Hyun Kim et al demonstrated that GA reduces histamine release from MCs induced by compound 48/80 or immunoglobulin E (IgE),157 regulates cAMP and intracellular calcium levels, inhibits nuclear factor kB and p38 mitogen-activated protein kinase, and contributes to blocking the expression of pro-inflammatory factors. These actions mitigate in vivo allergic reactions, restore and enhance local immune function, strengthen the nasal mucosa’s resistance to pathogens, thereby reducing the incidence of AR.

Catechins

Catechins, classified as flavanols within the flavonoid family, are natural polyphenolic compounds found in various plants. Ongoing research has unveiled that catechins possess a range of pharmacological effects, including anti-inflammatory, antibacterial, antiviral, and antioxidant properties.174,175 Recent experimental studies utilizing catechins to treat AR in mice have demonstrated significant improvements in behavioral responses, reductions in leukocyte counts, inhibition of inflammatory cell infiltration, and alleviation of local inflammation symptoms.158 Furthermore, catechins have been shown to inhibit the NF-κB pathway and reduce the degradation of IκBα proteins while influencing upstream regulators of TSLP in epithelial cells. This modulation leads to decreased levels of TSLP and