TLR1 is expressed in myeloid cells, T and B cells, natural killer cells, and microglia and astrocytes and is involved in the recognition of cell wall constituents, including viral proteins and bacterial lipoproteins (32–34). The expression of TLR1 on peripheral blood mononuclear cells is significantly higher in patients with asthma than that in healthy individuals, indicating that TLR1 plays a role in the pathogenesis of asthma (35). However, TLR1/2 mRNA treatment has demonstrated protective effects on asthma induced by house dust mites in mice (36).

Furthermore, the polymorphism of the TLR1 gene is associated with the risk of asthma. Kormann et al. confirmed that the TLR1 single-nucleotide polymorphisms (SNPs), such as rs5743594, rs5743595, and rs4833095, have a protective effect on atopic asthma (37), but the variant TLR1 rs5743618 may increase the risk of asthma at the age of 11–13 years after infant bronchiolitis (38, 39). The aforementioned studies indicate that, on the one hand, TLR1 recognizes pathogens and is highly expressed in patients with asthma, suggesting its potential role in promoting inflammation or in the pathogenesis of asthma, but on the other hand, the TLR1/2 signaling pathway has been confirmed to have protective effects on asthma, and TLR1-specific gene polymorphisms are associated with either protection against asthma or risk of asthma. These seemingly contradictory findings suggest that the specific role of TLR1 in asthma may be regulated by multiple factors, and it is worthy of further in-depth exploration.

TLR2 is broadly expressed on the surface of diverse cell types, including both immune cells, such as myeloid cells and T cells (40, 41) and non-immune cells, such as epithelial, endothelial, and nerve cells (42). Typically, TLR2 forms functional heterodimers with TLR1 or TLR6 on the cell surface. This heterodimerization not only broadens the spectrum of PAMPs recognized by TLR2 but also diversifies the resulting downstream signaling cascades (43). This widespread distribution underscores the significant role of TLR2 in linking innate immunity, tissue homeostasis, and disease pathogenesis. TLR2 transduces signals from various molecules, including lipoproteins and cell wall components of Gram-positive bacteria, peptidoglycans and lipoarabinomannan from mycobacteria (44, 45), and the high mobility group protein B1 (HMGB1) (46).

In the context of asthma, the role of TLR2 is particularly evident. Pauline et al. demonstrated that specific recognition of Aspergillus fumigatus conidia PAMPs by the TLR2/MyD88 pathway elevates IL-10 levels while reducing lung eosinophilia and type 2 responses (47). Furthermore, microRNA-146a (miR-146a), a key regulatory factor in ovalbumin (OVA)-induced allergic asthma models, alleviates asthma symptoms by modulating the TLR2 signaling pathway (48). Genetic studies reveal that TLR2 deficiency enhances IgE production but suppresses IgG1 class switching following OVA sensitization (49). Specific polymorphisms, such as TLR2 rs3804100, are associated with allergic asthma (50), whereas TLR2 rs4696480 shows a significant link to asthma susceptibility (51). Interestingly, genetic variants within the TLR2-associated heterodimer network (including TLR1 and TLR6) confer strong protection against atopic asthma (37).

Collectively, these studies suggest that TLR2 predominantly exerts a protective role in asthma. Its activation can mitigate allergic inflammation through multiple mechanisms, including inhibiting type 2 responses, regulating antibody class switching, and inducing anti-inflammatory factors such as IL-10. However, the precise impact of TLR2 activation likely depends on factors such as the timing of microbial exposure and individual genetic background.

IgE and its high-affinity Fc receptor, FcϵRI, are pivotal in asthma pathogenesis. Genome-wide association studies have shown that the Fcϵ receptor Ia (FCER1A) gene, encoding the ligand-binding subunit of the high-affinity IgE receptor, is the main susceptibility locus for serum IgE levels. Genetic polymorphisms of the FCER1A gene may affect IgE levels related to asthma (52). In atopic dermatitis, an interaction between the TLR2 rs4696480 locus and the FCER1A rs2252226 locus has been linked to disease severity (53). Concurrently, TLR2 activation induces FcϵRI downregulation in human Langerhans cells (54). A suggested mechanism posits that TLR2 regulates the type 1 and type 2 balance. Nevertheless, this is complicated by the fact that TLR2 drives a type 1 deviation during the chronic phase of atopic dermatitis (55), contrasting with generally type 2-polarized immune response of asthma (56). TLR2 modulates FcϵRI expression in airway antigen-presenting cells. If TLR2 downregulates FcϵRI, it could attenuate IgE-mediated mast cell activation, thereby mitigating acute allergic responses. The relevance of the TLR2 rs4696480 polymorphism established in atopic dermatitis (57) raises the possibility of a similar effect in asthma, potentially influencing IgE levels via FCER1A expression regulation. However, further experimentation is required to confirm the direct regulatory effect of TLR2 on FcϵRI expression in the context of asthma.

TLR3 is located on the endosomal membranes of epithelial cells, neuroglial cells, neurons, and dendritic cells and can recognize viral double-stranded RNA, polyinosinic:polycytidylic acid. This receptor plays a crucial role in autoimmune diseases, viral infections, and the development of asthma (58–61). Abnormal activation of the TLR3 signaling pathway and excessive activation of its downstream signaling factor TRIF can trigger the recruitment of local inflammatory cells and excessive synthesis of proinflammatory mediators, thereby causing various inflammatory diseases including asthma (62). In animal models of asthma, stimulation of the TLR3/TRIF signaling pathway has been demonstrated to exacerbate airway inflammation, promote inflammatory cell infiltration, and worsen the severity of the asthma response (62). After TLR3 is activated, significant infiltration of inflammatory cells occurs in the lung tissue, which subsequently leads to epithelial damage and histamine release. Excessively released inflammatory mediators promote the migration and differentiation of lung fibroblasts and airway matrix cells, enhance extracellular matrix synthesis, and cause thickening and fibrosis of the airway wall, thereby further exacerbating the severity of asthma (62, 63). Sugiura et al. also confirmed that in asthma, activation of the TLR3/TRIF signaling pathway could affect airway remodeling by promoting the differentiation of myofibroblasts (64).

Furthermore, studies have also revealed the important role of the TLR3/NF-κB/IRF3 signaling pathway in the progression of viral-induced asthma (65, 66). For example, respiratory syncytial virus infection could upregulate the expression of TLR3, resulting in the overexpression and release of downstream inflammatory factors through the TLR3/NF-κB/IRF3 pathway in asthmatic mice; this process also enhances extracellular matrix synthesis, further aggravating asthma symptoms (67). Additionally, Ramu et al. found that the TLR3/TAK1 signaling pathway regulates the production of IL-33 in bronchial smooth muscle cells during nasal rhinovirus infection (68).

The contribution of TLR3 genetic variants to asthma pathogenesis remains an area of investigation, with evidence showing some heterogeneity. While one study in Chinese Han patients failed to detect a significant association between TLR3 SNPs and asthma susceptibility or severity (69), other investigations have reported positive links. Specifically, research on aspirin-tolerant asthma found that TLR3 polymorphisms, particularly -299698G>T and 293391G>A [Leu412Phe] were associated with various respiratory phenotypes encompassing asthma (70). Moreover, both Canadian family-based analyses and an Australian population-based case-control study associated the rs1519309 SNP within TLR3 with atopic asthma (71). Functionally, TLR3 is known to mediate viral recognition and subsequent inflammatory responses, processes that are believed to significantly influence asthma progression. Indeed, excessive activation of TLR3 has been shown to exacerbate inflammation and fibrosis. However, despite correlations observed between TLR3 genetic variants and various asthma and allergic phenotypes, the specific impact of these variants on asthma susceptibility and severity exhibits considerable heterogeneity across different populations and studies. This inconsistency underscores the complex and multifactorial nature of TLR3’s regulation within the context of asthma pathogenesis.

TLR4 is primarily expressed on myeloid-derived immune cells, including macrophages, monocytes, and dendritic cells (72–74) and also present on non-immune cells such as microglia, astrocytes, neurons, and endothelial cells (75). The outer membrane component of Gram-negative bacteria, lipopolysaccharide (LPS), serves as a specific ligand for TLR4 (76). Upon LPS binding, TLR4 activates the MyD88-dependent signaling pathway, triggering a cascade that activates downstream kinases. This cascade facilitates the nuclear translocation of NF-κB-associated factors, enabling their regulation of proinflammatory gene expression, particularly for IL-6, IL-1β, and tumor necrosis factor-α genes (77). TLR4 triggers immune responses via two distinct signaling pathways: the TRIF-dependent and the MyD88-dependent pathways (78). Stimulation of the MyD88/NF-κB pathway enhances the production of proinflammatory cytokines (77, 79), whereas the TRIF pathway contributes to asthma exacerbation (80).

Research by McAlees JW et al. highlights the differential roles of TLR4 depending on the cell type involved. Their findings indicate that TLR4 expression in hematopoietic cells is crucial for neutrophilic airway inflammation, observed both following LPS exposure and in Th17-driven neutrophilic responses to house dust mite lysates and OVA. In contrast, TLR4 expression by airway epithelial cells plays a key role specifically in robust eosinophilic airway inflammation when these same allergens are used for sensitization and challenge (81). However, broader research indicates that TLR4 activation predominantly promotes eosinophilic responses and type 2 inflammation. Specifically, studies demonstrate that LPS binding to TLR4 promotes type 2 immune responses, thereby exacerbating allergic respiratory inflammation (79). The cytokines and chemokines produced during type 2 responses are pivotal in asthma development, facilitating eosinophil recruitment and survival, promoting antigen-specific antibody production, and inducing mucus cell proliferation in the bronchial epithelium (82). Beyond recognizing exogenous microbial PAMPs, TLR4 also detects endogenous DAMPs (83), including HMGB1 and cellular heat shock proteins (84). The interaction between TLR4 and HMGB1 activates the NF-κB pathway, leading to the synthesis of inflammatory mediators and exacerbation of asthma symptoms. Furthermore, suppression of HSF1 has been shown to worsen OVA-induced airway inflammation and hyperresponsiveness in mice, likely through HMGB1 upregulation and activation of the TLR4/MyD88/NF-κB pathway (85). Aberrant activation of the TLR2/TLR4 signaling pathway can result in the excessive production of inflammatory factors, such as IL-1β, IL-5, IL-8, IL-4, and IL-13, and chemotactic mediators by neutrophils, monocytes, and type 2 lymphocytes within the airway. These mediators recruit neutrophils, stimulate goblet cell hyperplasia, and amplify the type 2 immune response. Consequently, this cascade leads to the synthesis of allergen-specific IgE and IgG1, increasing airway hyperresponsiveness and potentially triggering acute asthma attacks (77, 86). Collectively, these studies demonstrate that TLR4, by bridging innate and adaptive immunity and responding to diverse stimuli (both PAMPs and DAMPs), plays a multifaceted role in asthma pathophysiology, influencing inflammation, immune deviation, inflammatory cell recruitment, airway remodeling, and hyperresponsiveness, establishing TLR4 as a critical regulatory node.

Additionally, polymorphisms in the TLR4 gene are significantly correlated with an elevated risk of asthma (87). TLR4 rs4986791 was found to be significantly associated with asthma susceptibility in a meta-analysis, especially in the Asian population (88). The findings from a comparative analysis demonstrate an association between the TLR4 rs4986791 variant and bronchial asthma risk among Chinese children (89). TLR4 rs1927911 is also associated with antibiotic exposure and bronchiolitis in childhood asthma (90). Although mice expressing cosegregating SNPs D298G and T399I in TLR4 have enhanced responses to the house dust mite allergen, their responses to OVA and LPS were not significant (91). These findings indicate that TLR4 polymorphic variants exhibit differential interactions with allergic stimuli, potentially modulating immune responses in a genotype-dependent manner. Although existing studies (including population association analyses and animal models) have provided strong evidence for the role of TLR4 in asthma, there are still some limitations. For instance, population studies are mostly correlational analyses, making it difficult to determine causal relationships.

TLR5 is a receptor that recognizes bacterial flagellar proteins and is not only expressed on the surface of myeloid cells, but also on the surface of epithelial cells, microglia, and astrocytes. It is abundantly expressed in airway epithelial cells and weakly expressed in alveolar macrophages (92). Shikhagaie et al. discovered that TLR5 is widely expressed in the lungs, but its expression is reduced in severe asthma. In patients with severe asthma, a significantly negative correlation is present between intracellular TLR5 immunoreactivity and IgE (93). This might be due to the fact that patients with severe asthma have insufficient TLR signaling during viral or bacterial infections, resulting in a reduced anti-allergic type1 response and a weakened or impaired immune defense mechanism. The binding of the flagellin protein to its receptor TLR5 affects the transcriptional profile of human primary epithelial cells, including genes encoding chemokines, matrix metalloproteinases, and antimicrobial molecules, thus inducing the expression of proinflammatory cytokines and chemokine mRNAs and promoting the secretion of granulocyte-macrophage colony-stimulating factor, C-X-C motif chemokine ligand-5, C-C motif chemokine-5, and C-X-C motif chemokine ligand-10, which may contribute to airway inflammation and remodeling (94). Bacterial flagellin in the household environment initiates allergic responses to indoor allergens in a TLR5-dependent manner, thereby promoting the development of allergic asthma (92). In OVA-specific asthmatic mouse models, the activation of TLR5 by bacterial products (flagellin) exacerbates allergic airway inflammation (95).

While the recognition of flagellin generally of TLR5 promotes inflammation in asthma, genetic variations in the TLR5 gene reveal a more complex picture, sometimes offering protection. For instance, a dominant-negative polymorphism (rs5744168) is linked to alleviated asthma symptoms in patients (95). Interestingly, another TLR5 variant (rs5744174) might increase susceptibility to bronchiolitis not caused by respiratory syncytial virus (non-RSV bronchiolitis), but this variant does not appear to be associated with the subsequent development of asthma following such bronchiolitis (96).

TLR6 is mostly present on the cell membrane of myeloid cells and also expressed on epithelial cells, microglia, and astrocytes, where it forms heterodimers with other TLRs, particularly TLR2 (30). TLR6 forms heterodimers with TLR2 to recognize specific pathogen-associated components such as diacyl lipopeptides, lipoteichoic acid, and zymosan. Chun et al. examined the expression of TLR6 on CD14^high cells in patients with asthma and found that TLR6 expression in the asthma group was significantly lower than that in the control group, and the expression level of TLR6 was statistically significant among patients with mild, moderate, and severe asthma (35). In the asthma model of TLR6^-/- mice induced by fungal or house dust mite antigens, airway hyperresponsiveness, inflammation and remodeling worsened significantly, but the levels of IL-23 and IL-17 in the whole lung decreased significantly. Exogenous IL-23 treatment restored the production of IL-17A in asthma TLR6^-/- mice, significantly reducing airway hyperresponsiveness, inflammation and pulmonary fungal burden (97). This indicates that TLR6 may play a certain protective or regulatory role in asthma through the IL-23/IL-17 pathway, and its low expression may be associated with the aggravation of asthma.

In the development of asthma, TLR6 not only regulates the immune response through signaling pathways, but its genetic polymorphisms also jointly influence the susceptibility to the disease along with environmental exposure. In children exposed to a farm environment, those carrying the TLR6 rs1039559 T-allele and the TLR6 rs5743810 C-allele have a lower risk of early-onset asthma compared with healthy children (98). The polymorphism of TLR6 rs5743810 has some exploratory correlation with airway reactivity (99) and a weak correlation with childhood asthma (100). Perhaps this conclusion (such as reducing risks) requires a larger sample size and more rigorous environmental control for verification.

TLR7 is mostly expressed in human plasmacytoid dendritic cells and, to a lesser degree, T cells, B cells, neutrophils, eosinophils, and mononuclear macrophages (101). TLR8 is predominantly expressed in myeloid dendritic cells, neutrophils, and monocytes (102). TLR7 and TLR8 recognize single-stranded RNA as their natural ligand (24). Yan et al. employed a combined analysis approach based on the gene expression profiles of induced sputum derived from the comprehensive Gene Expression Omnibus databases (GSE76262 and GSE137268) and found that reduced TLR7 expression correlated with airway eosinophilic inflammation and lung function in asthma (103). In a mouse asthma model induced by dust mites, TLR7 expression was significantly downregulated. TLR7-deficient asthmatic mice exhibited substantial inflammatory cell infiltration in the lungs, accompanied by elevated levels of IL-4, IL-10, IL-12, and IFN-γ, as well as increased phosphorylation of inhibitory κB kinase-α and NF-κBp65 expression. Importantly, the administration of a TLR7 agonist reversed these detrimental effects, suggesting that TLR7 upregulation mitigates asthma inflammation by inhibiting the NF-κB signaling pathway (104). Consistent with this finding, another study demonstrated that the interaction between TLR7 and its ligand alleviates eosinophilia and allergen-induced airway hyperreactivity in asthma, a process mediated by MyD88-dependent but MK2-independent signaling pathways (105). However, the interaction of TLR8 with its ligand promotes neutrophil proliferation, induces the secretion of chemokines and neutrophil elastase, triggering an airway inflammatory response that may counteract the protective effect of TLR7 (106). In rhinovirus-induced asthma, the IFN response is defective. Administration of the TLR7/8 agonist R848 to peripheral blood mononuclear cells from preschool asthmatic children was found to decrease IFN-αR mRNA levels while inducing IFN-λR1 mRNA. These findings suggest that targeting TLR7/8-mediated modulation of type I/III IFN signaling pathways could represent a novel therapeutic strategy to enhance antiviral immunity in pediatric asthma (107).

Although the available evidence suggests a protective role of TLR7 and a proinflammatory effect of TLR8, several key issues require further exploration. Firstly, the expression and function of TLR7/8 are likely influenced by factors including cell type, the underlying inflammatory milieu (e.g., eosinophilic versus neutrophilic predominance), and disease stage. Furthermore, the observed correlations in the literature—such as the association between TLR7 expression and eosinophilic inflammation—are not yet established as causal relationships. Secondly, although evidence supports the proinflammatory properties of TLR8, whether it directly counteracts the protective effects of TLR7 within the human body, and if this interaction is truly and universally significant, requires further direct investigation.

This complexity is further highlighted by genetic association studies. For example, a study found that an increased frequency of TLR7 gene polymorphisms is correlated with a higher risk of asthma in preschool children following infant bronchiolitis (108, 109). Conversely, although case-control and case-only studies found no significant association between TLR7 and TLR8 genetic variations and overall asthma susceptibility, these same variations were linked to asthma-related phenotypes. Specifically, polymorphisms in both TLR7 and TLR8 were associated with eosinophil count, serum IgE levels, lung function, and asthma severity (110). This suggests that genetic variations in TLR7 and TLR8 may indeed contribute to asthma pathogenesis, particularly influencing disease characteristics rather than initial susceptibility.

TLR9 is mainly found in monocytes, plasmacytoid dendritic cells, B cells, microglia, astrocytes, and neurons. It recognizes self-DNA within immune complexes and unmethylated CpG DNA from viral, bacterial, and parasitic sources (100). When TLR9 binds to unmethylated CpG DNA on the surface of plasmacytoid dendritic cells and B cells, it can trigger type 1 immune responses and promote the differentiation and development of regulatory T cells. This process is accompanied by the production of IFN-γ and the release of IL-10 and transforming growth factor-β, and these cytokines work together to inhibit type 2 cell responses and alleviate asthma symptoms (111). Consistent with this anti-inflammatory potential, intranasal administration of CpG can alleviate experimental fungal asthma in a TLR9-dependent manner (112).

However, the role of TLR9 in asthma is complex. Some studies suggest that the TLR9–IL-2 axis may contribute to the deterioration of allergic asthma by exacerbating excessive IL-17A production (113). Furthermore, evidence indicates that TLR9 may regulate allergic airway inflammation by activating the NLRP3 inflammasome and inducing oxidative stress (114). Despite these complexities, TLR9 agonists hold promise as potential immunomodulators or vaccine adjuvants, exhibiting promising prospects in the research of immunotherapy for allergic diseases (115).

Additionally, genetic factors play a role, as specific TLR9 polymorphisms may influence the clinical manifestations of childhood asthma. For instance, the TLR9 rs187084 polymorphism is associated with the control of childhood bronchial asthma to some extent (116), and the overall TLR9 SNP profile is significantly correlated with susceptibility to childhood asthma (109). This genetic link is further supported by studies on bronchiolitis-induced wheezing, which suggest that the TLR9 rs187084 gene polymorphism may be a potential genetic factor in its occurrence and development (117).

TLR10 is a recently identified member of the human TLR family. Currently, it is regarded as the only orphan receptor in this family, and its exact function and natural ligands remain unclear (118). TLR10 is expressed as a type I transmembrane protein in various immune cells such as B cells and dendritic cells (119). Its mRNA is highly expressed in lymphoid tissues such as the spleen, lymph nodes, thymus, and tonsils.

Although there is a lack of in-depth analysis of its biological function, genetic studies have found that the polymorphisms of the human TLR10 gene are associated with various disease states, including bacterial infections, asthma, autoimmune diseases, and cancer (120–122). Lazarus et al. confirmed that TLR10 gene variations are related to asthma susceptibility (122). In particular, TLR10 is associated with the occurrence of bronchiolitis post-asthma, which may increase the risk of developing asthma in infants who have suffered from bronchiolitis before the age of 11–13 (38, 108, 116). These findings suggest that TLR10 may play a potential role in the pathogenesis of respiratory diseases, especially in the onset of childhood asthma, and warrant further in-depth research.

The TLR signaling pathway typically initiates downstream signal transduction through two major adaptor proteins: MyD88 and TRIF. Among these, MyD88 plays a central role in signal transduction and is essential for the activation of most TLRs (123). Structurally, MyD88 contains three distinct functional domains: an N-terminal death domain, a central intermediate region, and a C-terminal Toll/IL-1 receptor (TIR) domain. The cytoplasmic region of TLRs shares significant homology with the TIR domain of the IL-1 receptor (IL-1R) family, which is critical for downstream signaling. TIR domain-containing adaptor proteins are essential for TIR-mediated signaling, as they are required for the activation of TLR4 and TLR2 pathways, but not for TLR5, TLR7, or TLR9 (124, 125).

Most TLRs, including TLR1/2, TLR4, TLR5, TLR6/2, TLR7/8, and TLR9, transmit signals through the MyD88-dependent pathway (126). This pathway activates the NF-κB and MAPK signaling cascades, leading to the production of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α (47, 86, 104, 115, 127). In the context of asthma, dysregulation or aberrant activation of the MyD88-dependent signaling pathway has been implicated in the development of immune imbalance, characterized by enhanced type 2 immune responses, suppression of regulatory T cell function, and exacerbated airway inflammation and remodeling. Specifically, TLR4, which recognizes both exogenous ligands such as LPS from Gram-negative bacteria and endogenous danger signals like HMGB1, activates the NF-κB and MAPK pathways via the MyD88-dependent pathway. This activation promotes Th2 cell differentiation and IgE production, which are key features of allergic asthma (85, 86). Similarly, TLR2/1 and TLR2/6, which recognize bacterial lipoproteins and peptidoglycans, also signal through the MyD88 pathway, inducing the expression of IL-12 and IFN-γ. Under certain conditions, this may suppress type 2 responses, but excessive activation can lead to chronic inflammation (47, 49). Furthermore, TLR7/8, which detects single-stranded RNA from viruses, activates the MyD88 and IRF7 pathways, resulting in the production of IFN-α/β and IL-12. This signaling is particularly relevant in viral-induced asthma, highlighting the critical role of MyD88-dependent pathways in linking microbial exposure to immune dysregulation in allergic diseases (105, 107).

TRIF is extensively expressed across various cell types and is located within the cytoplasm under resting conditions. The TRIF signaling pathway is shared between TLR3 and TLR4 (128). Specifically, TRIF can directly interact with TLR3 or associate with TLR4 indirectly through the TRIF-associated adaptor molecules (6). Upon binding to TLR4, activation of the TRIF pathway occurs within the endosomal compartment following TLR4/MD2 complex internalization. Activation of the TRIF pathway involves activation of tumor necrosis factor receptor-associated factor 3, induction of nuclear translocation of IRF3, and recruitment of IFN-β. These processes are mediated by TRIF-associated adaptor molecules and TIR domain-containing adaptor proteins (129). The TRIF-dependent pathway can activate IRF3 and NF-κB, inducing proinflammatory cytokine gene expression and type I IFN production. This mechanism exacerbates asthma (130).

Although the role of TLRs in asthma has been extensively investigated, several controversies remain unresolved, highlighting the complexity of TLR-mediated immune regulation in allergic diseases. First, some TLRs exhibits a dual and context-dependent role in asthma: while it can drive pro-inflammatory responses by activating NF-κB and MAPK pathways, it may also exert protective effects (95, 96). This duality underscores the need for a more nuanced understanding of functional outcomes of TLRs in different disease contexts. Second, cross-regulation among TLR signaling pathways adds another layer of complexity. TLRs can interact in both synergistic and antagonistic manners, leading to divergent immune responses. Such interactions may contribute to the heterogeneity of asthma phenotypes and complicate the interpretation of experimental findings (105, 106). Finally, individual variability and epigenetic regulation further complicate the picture. The activity of TLR signaling pathways may be influenced by epigenetic modifications which may alter gene expression and immune cell function. These factors not only contribute to inter-individual differences in disease susceptibility but also highlight the importance of integrating epigenetic perspectives in future TLR research.