Genetic and Epigenetic Interconnections Between Atopic Dermatitis, Allergic Rhinitis, and Rhinitis with Nasal Polyps

Abstract

Background: Atopic dermatitis (AD), allergic rhinitis (AR), and chronic rhinosinusitis with nasal polyps (CRSwNP) represent interconnected conditions within the spectrum of type 2 inflammatory diseases. While these conditions share common genetic and epigenetic pathways, the precise molecular mechanisms remain underexplored. Methods: This review integrates the latest insights on the genetic and epigenetic factors linking AD, AR, and CRSwNP, focusing on genome-wide association studies, DNA methylation patterns, histone modifications, and microRNA regulation. Results: In all three conditions, epigenetic modifications, including DNA methylation (Me) and histone acetylation (Ac) and methylation, regulate inflammatory and barrier-related genes, influencing disease severity. Notably, miRNAs such as miR-146a and miR-155 play pivotal roles in modulating inflammation across all three diseases, while disease-specific miRNAs contribute to airway remodeling (miR-125b and miR-21 in AR and CRSwNP). Emerging evidence underscores the role of microbiome-driven inflammasome activation and matrix metalloproteinases (MMP-2, MMP-9, and MMP-12) in perpetuating chronic inflammation and remodeling. Conclusions: The interplay between genetic predispositions, epigenetic modifications, and exposomal factors underscores the systemic nature of type 2 inflammation. A deeper understanding of these interconnected mechanisms could lead to transformative, personalized diagnostic and therapeutic advancements.

1. Introduction

Atopic dermatitis (AD), allergic rhinitis (AR), and chronic rhinosinusitis with nasal polyps (CRSwNP) represent distinct yet interconnected conditions united by underlying type 2 inflammation. This systemic inflammatory process is driven by dysregulated immune responses, characterized by elevated immunoglobulin E (IgE) levels and type 2 T-helper (Th2) cytokines, such as IL-4, IL-5, IL-13, and IL-31 as key mediators [1,2,3]. Exposomal factors such as urbanization, pollution, and allergen exposure have profound effects on these conditions [4,5].

The “atopic march” describes a well-documented progression of allergic diseases, starting with AD and food allergies in early childhood and often leading to AR and asthma later in life [6]. Approximately 50% of patients with AD develop asthma and subsequently AR; however, these statistics may be skewed by studies focused on severe cases [7]. This progression suggests that AD, AR, and asthma share underlying mechanisms, primarily involving immune hypersensitivity mediated by increased IgE. This hypersensitivity drives allergic reactions across skin, gastrointestinal, and respiratory systems, with Th2 cells and mediated cytokines [1,2,3,8]. Therefore, recognizing type 2 inflammation in patients with both skin and respiratory symptoms is increasingly important for guiding targeted therapies.

Genetic factors play a significant role in the link between AD and AR. Well-established mutations in the filaggrin (FLG) gene, along with other genetic variants, significantly increase the risk of AR, independent of AD severity or age of onset [9,10,11]. Studies indicate that AR is more prevalent in patients with early-onset AD (<2 years), likely due to elevated IgE levels in these cases [12,13]. IgE plays a pivotal role in both conditions by facilitating mast cell degranulation and histamine release upon allergen exposure. In AD, IgE levels are frequently elevated, particularly in individuals with an extrinsic phenotype driven by environmental allergens [14,15]. This IgE-mediated sensitization is observed in early-onset AD, which precedes AR as part of the atopic march [16,17]. The increased IgE response in AD and AR is regulated by IL-4 and IL-13, promoting the IgE class switch [18]. Genetic variants in IL-4Ra, STAT6, and FCER1A (a high-affinity IgE receptor) have been associated with both conditions [18,19]. AR symptoms, including sneezing, nasal pruritus, and congestion, are commonly present in AD patients sensitized to environmental allergens such as dust mites and pollen.

AD is a chronic inflammatory skin disorder with a considerable global burden and an etiopathogenesis that combines genetic and environmental factors [20]. While mutations are established risk factors, the increased AD prevalence in industrialized regions suggests that lifestyle and the environmental exposome also play a role [5]. Epigenetics refers to the mechanisms by which genes interact with environmental factors and plays a crucial role in disease development and progression [21,22]. Key epigenetic mechanisms, such as DNA methylation and histone modifications, influence the activation or silencing of genes, contributing to the pathogenesis of AD [23,24,25,26,27]. Bioinformatics and high-throughput methodologies, including chromatin immunoprecipitation (ChIP) and next-generation sequencing (NGS), have helped to further the understanding of these epigenetic changes across cell types, presenting novel therapeutic avenues via targeting epigenetic regulation and potentially improving AD management [23,28,29].

Similarly, chronic rhinosinusitis (CRS) is a prevalent otorhinolaryngologic disorder characterized by prolonged inflammation of the paranasal sinus mucosa for at least 12 weeks [30]. It is classified into two types: CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP) [31]. Among these, CRSwNP represents a distinct phenotype characterized by the formation of benign, edematous nasal polyps and a dominant type 2 inflammatory response [32]. Affecting 2.3–2.7% of the population, CRSwNP presents significant clinical challenges due to its chronic nature and resistance to conventional therapies [33]. The pathophysiology of CRS involves genetic predispositions, bacterial infections, occupational exposure, and environmental factors. Epigenetic modifications, particularly DNA methylation, histone modifications, and regulation by non-coding RNAs (ncRNAs) and microRNAs, influence gene expression and CRS susceptibility [34,35]. Dysregulation of epigenetic patterns and signatures contributes to variability in disease presentation even among genetically identical individuals, such as monozygotic twins, who may develop different conditions due to environmental, nutritional, or psychosocial influences [36,37]. Additionally, epigenetics can impact immune cell function, particularly T lymphocytes, potentially leading to allergic diseases such as AR [38].

Recent reports emphasize the role of epigenetic factors in nasal polyps, highlighting their importance in regulating the cell cycle, cellular proliferation, inflammation, and immune responses. This growing body of research on genetic and epigenetic links among AD, AR, and CRS with nasal polyps is paving the way for more precise, individualized therapies targeting underlying molecular mechanisms (Figure 1).

Figure 1. Pathophysiological and molecular mechanisms linking atopic dermatitis (AD), allergic rhinitis (AR), and chronic rhinosinusitis with nasal polyps (CRSwNP). The diagram illustrates the shared Th2-driven inflammatory pathways in AD, AR, and CRSwNP. The top schematic represents the nasal epithelium in AR and CRSwNP, while the bottom represents the epidermis and dermis in AD. In both tissues, environmental triggers such as allergens and bacteria such as Staphylococcus aureus (S. aureus) stimulate keratinocytes and nasal epithelial cells to release thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and periostin, initiating a Th2 response. This leads to the secretion of IL-4, IL-5, and IL-13 which drive eosinophilic inflammation, promote B-cell class switching to IgE production, and activate mast cells, resulting in chronic inflammation. The upper right panel illustrates a dysregulated immune microenvironment in AR and CRSwNP, emphasizing the role of IgE, IL-33 overexpression, and eosinophil recruitment in promoting chronic inflammation and nasal polyp growth. The lower right panel focuses on AD pathogenesis, emphasizing the role of genetic factors such as filaggrin (FLG) deficiency. In all three conditions (AD, AR, and CRSwNP), epigenetic modifications, including DNA methylation (Me) and histone acetylation (Ac), regulate inflammatory and barrier-related genes, influencing disease severity. Notably, miRNAs such as miR-146a and miR-155 play pivotal roles in modulating inflammation across all three diseases, while disease-specific miRNAs contribute to airway remodeling (miR-125b and miR-21 in AR and CRSwNP). Matrix metalloproteinases (MMP-2, MMP-9, and MMP-12) and inflammasome activation further promote tissue remodeling and chronic inflammation, particularly in CRSwNP. These interconnected molecular mechanisms amplify chronic skin and airway inflammation, underscoring their role in the shared pathogenesis of these disorders. (Created in BioRender. (2025) https://BioRender.com/q78g867 Accessed on 4 March 2025.).

2. The Genetics and Epigenetics of Atopic Dermatitis (AD)

AD is a chronic inflammatory skin disorder driven by complex interactions between genetic predisposition and environmental influences [27,39,40,41]. Genetically, AD is a multifactorial and inheritable condition with over 70 associated genes identified across diverse populations, classified into five key groups that influence its pathogenesis. These include genes affecting epidermal barrier dysfunction, innate and adaptive immune responses, cytokines, environmental responses, vitamin D metabolism, and filaggrin and related genes [42,43,44].

Genetic mutations affecting the epidermal barrier function lead to compromised skin integrity, facilitating easier entry for allergens and pathogens [42,43,44]. Among these, loss-of-function mutations in FLG represent the most significant genetic AD risk factor, though immune-related variants also play key roles [45]. Variations in innate immune response genes can hyper-activate the toll-like receptor (TLR) system and cause the excessive production of Th2 cytokines, such as IL-4, IL-5, IL-13, and IL-31, leading to chronic inflammation. Additionally, adaptive immune response genes may impact regulatory T lymphocytes, increasing the likelihood of immune dysregulation and persistent skin inflammation. During chronic AD stages, key cytokine profiles secreted by Th1, Th17, and Th22 become particularly relevant in sustaining inflammation [8,27,39,42,46,47,48,49,50,51,52,53,54].

Genes encoding cytokines, such as IL-25, TSLP, and IL-33, are activated by environmental stressors (e.g., UV exposure and mechanical injury), which further contribute to inflammation and AD flares [27,39,46,47,55,56]. Single-nucleotide polymorphisms (SNPs) in at least 34 loci and 46 genes contribute to AD susceptibility across different populations [57,58]. Notably, variants in genes involved in vitamin D metabolism and the synthesis of its receptor have been implicated in AD, suggesting that vitamin D pathways may influence susceptibility to inflammation and skin barrier dysfunction [27,40,48,59].

Beyond FLG, other significant genetic factors associated with AD include its upstream regulator OVOL1 and the cytokine IL-13, both of which influence skin barrier integrity and immune responses [49,60,61]. Genome-wide association studies (GWASs) have confirmed the association between AD and the FLG locus while identifying additional susceptibility loci at 2q12.1, 3p21.33, 3q13.2, 5q22.1, 5q31.1, 6p21.33, 7p22, 10q21.2, 11p15.4, 11q13.1, 11q13.5, 19p13.2, and 20q13.33 [62,63,64]. Some of these loci exhibit population-specific associations, with 6p21.33, 10q21.2, and 2q12.1 identified in both European and Japanese analyses, while 20q13.33 showed associations in Chinese and European populations. Additionally, loci at 3q13.2 and 11p15.4 appeared to be Japanese-specific [65,66,67]. A multi-ethnic meta-analysis of GWASs identified 10 susceptible gene loci for AD in addition to the 21 previously identified, emphasizing the role of these genes in the disease’s pathogenesis. Four (11q24.3, 10p15.1, 8q21.13, and 2p25.1) were previously linked to self-reported allergies, and two variants (5p13.2 and 2p25.1) showed significant heterogeneity between European and non-European studies [66]. A recent transcriptome-wide study from our group identified 52 novel AD risk genes enriched in skin and inflammation pathways. Large-scale RNA-seq confirmed 16 hub genes, including transcription factors FOSL1 and RORC [68].

Matrix metalloproteinases (MMPs), enzymes involved in tissue remodeling and immune cell migration, are also upregulated in AD lesions, especially MMP-9 and MMP-12. Elevated MMP activity disrupts normal skin architecture, exacerbating inflammation and skin barrier dysfunction, which are central to AD pathology [69,70] (Figure 1).

2.1. Epigenetic Patterns in AD Pathogenesis

Epigenetics play a crucial role in regulating gene expression in AD, bridging environmental factors and genetic susceptibility. Epigenetic mechanisms such as DNA methylation and histone modification modulate gene expression in a dynamic way without changing the DNA sequence itself, impacting processes related to keratinocyte function, immune responses, and inflammation.

DNA methylation typically suppresses gene expression by adding methyl groups to CpG-rich regions in promoters, thereby influencing immune response and skin cell behavior [42]. In AD patients, significant differential DNA methylation changes have been identified at 19 CpG sites, particularly in genes involved in keratinocyte differentiation and immune response, such as the S100A family, distinguishing AD-affected skin from healthy skin [24,41]. Additional AD-associated methylation changes include KRT6A and FLG [23,71].

Furthermore, the activation of the GATA3 transcription factor in Th2 lymphocytes results in cytokine production (IL-4, IL-5, and IL-13) by demethylating the promoters of the IL-4 and IL-13 genes, which impacts both immune and skin cell functions. CpG hypermethylation in IL-4 correlates with IgE levels, supporting Th2 immunity in AD [72]. This process is accompanied by increased methylation at the promoter of the IGF gene and decreased acetylation of histones in that region [42]. Extensive investigations have been conducted on the epigenetic changes experienced by pregnant women. Prenatal exposures, such as maternal smoking, allergies, and cytokine activity, can impact newborns’ DNA methylation, specifically at loci such as TSLP5’ the CpG island, and FOXP3, reducing regulatory T cell populations and increasing the risk of AD and related allergies in early childhood [41]. TSLP promoter hypomethylation is observed in AD lesions [73]. Histone modifications at the FOXP3 and RORC genes regulate Treg differentiation, influencing AD pathogenesis [74,75,76].

2.2. MicroRNAs and Immune Modulation

MicroRNAs (miRNAs) are small, non-coding RNAs that bind to mRNAs, leading to the degradation or inhibition of translation and thus regulating immune responses and skin barrier integrity, which are both involved in AD [27,42,59] (Figure 1). As such, miR-10a-5p regulates keratinocyte proliferation and differentiation while miR-29b has a role in apoptosis and barrier integrity [77,78,79].

It is known that distinct miRNA expression patterns and signatures exist in AD-affected skin compared to healthy skin, with miRNAs such as miR-155 found to be highly overexpressed in infiltrating T lymphocytes in AD lesions [80]. The upregulation of miR-155, partly driven by environmental allergens such as dust mites and staphylococcal antigens, intensifies inflammatory responses in the skin [41,81]. Moreover, elevated levels of miR-223 in the blood cells of AD patients and increased levels of histamine-N-methyltransferase (HNMT) affect histamine metabolism, further aggravating inflammation [82]. On the other hand, miR-335 is downregulated in lesions, and miR-124, a key NF-κB modulator, is also reduced in AD [83,84,85]. Additionally, miR-146a-5p also modulates responses via NF-κB and correlates with IgE levels, while miR-143 mitigates inflammation via IL-13Ra1 [86,87].

2.3. Linking Genetics, Epigenetics, and the Environment in AD

The pathophysiology of AD is shaped by genetic, epigenetic, and environmental factors that collectively influence immune dysregulation and epidermal barrier integrity. Advances in epigenetics and genetics provide a deeper understanding of AD, highlighting the potential of epigenetic markers, such as DNA methylation and miRNA expression, as tools for understanding disease progression and identifying therapeutic targets [21].

3. The Genetics and Epigenetics of Allergic Rhinitis (AR)

3.1. Genetics of AR

GWASs have identified key loci associated with AR susceptibility, many of which overlap with atopic and autoimmune conditions, reinforcing the interconnected nature of these diseases. These genetic insights shed light on the shared pathways that influence immune regulation, barrier function, and inflammation. Among these genes, significant ones include SDAD1, CXCL10, CXCL9, RANTES, CXCL11, IL1R1, IL13, IL18, IL21/IL2, IL23R, IL12RB1, IL27, C11orf30, SMAD3, TLR1, GATA3, and HLA-DQ [88].

The largest GWAS on AR identified 20 novel risk loci, some of which also overlap with atopy and other allergic conditions [66]. For example, BCAP (10q24.1) and MRPL4 (19p13.2) were identified in a Chinese cohort GWAS as commonly linked with both AR and atopy, reinforcing the genetic connections between these conditions. Additionally, genetic regions, including HLA-DQ and NPSR1, were also confirmed as being associated with AR, with the 19p13.2 locus influencing allergic responses via the soluble intercellular adhesion molecule-1 (sICAM-1) pathway [89,90]. A locus on chromosome 7p21.1 has shown associations with AR across multiple ethnic groups, indicating a broad relevance of these loci in AR susceptibility [90]. Variations in the IL4 gene (rs2243250) and the vitamin D receptor VDR (rs2228570) are also associated with AR risk [91,92]. SNPs in the TNF-α gene have been identified as high-risk factors for AR [93]. Newly identified loci, such as IL7R (5p13.2), which has been previously linked to eczema, implicate T- and B-cell receptor signaling in AR through Th2-driven processes via TSLP [66]. Additionally, SH2B3 (12q24.12) is associated with blood eosinophil counts and T cell inflammation [66,88].

Notable immune-related AR loci such as CXCR5 (11q23), which is crucial for B-cell migration, correlate with disease severity and therapeutic responses, suggesting their role as biomarkers for targeted therapies [94]. Furthermore, FCER1G (1q23.3) encodes a component of the IgE receptor essential for allergic responses, while NFκB1 (4q24) engages in inflammatory pathway activation [95]. Other key genetic factors include BACH2 (6q15), which regulates memory B and T cells, and LTK and TYRO3 (15q15.1), which modulate Th2 immunity and TLR signaling, respectively [96,97]. Additional loci of interest include SPPL3 and OASL (12q24.31), which regulate NK cell maturation and IFN-α signaling, respectively, along with RORA (15q22.2), which is implicated in Th2 lymphoid cell development and inflammation regulation [98,99,100,101].

3.2. Epigenetics in AR

Epigenetic modifications, encompassing DNA methylation, histone deacetylation, and miRNA regulation, play significant roles in the pathogenesis of AR. Recent studies reveal how these mechanisms orchestrate immune dysfunction, inflammation, and epithelial barrier disruption in AR [102] (Figure 1 and Figure 2).

Figure 2. Molecular and cellular mechanisms in atopic dermatitis (AD), allergic rhinitis (AR), and chronic rhinosinusitis with nasal polyps (CRSwNP), highlighting shared and unique findings. The outer ring depicts the distinct features of each condition. In AD, chronic Th2-driven inflammation results in periostin-mediated skin thickening, lichenification, and pruritus, exacerbated by Staphylococcus aureus (S.aureus) colonization. In AR, allergen exposure triggers IgE-mediated hypersensitivity, leading to periostin-mediated hyper-responsiveness (sneezing, congestion, and rhinorrhea) and epigenetic modulation of IL-33. In CRSwNP, eosinophilic nasal inflammation, goblet cell hyperplasia, biofilm-mediated chronicity, and fibrosis mediated by TGF-β and MMP activity lead to polyp formation. The shared findings in the center of the diagram emphasize the role of impaired skin and nasal epithelial barriers, dysregulated Th2 cytokine pathways (IL-4, IL-5, and IL-13), epigenetic modifications (methylation and histone acetylation), and specific miRNAs, such as miR-155 and miR-146a, in modulating inflammation, tissue remodeling, and disease chronicity across these conditions. The matrix metalloproteinase MMP-9 further contributes to extracellular matrix remodeling, affecting airway and skin integrity. Together, these processes underscore the interconnectedness of these Th2-skewed disorders.

3.2.1. DNA Methylation in AR

DNA methylation changes can differentiate allergic patients from healthy individuals and influence immune cell behavior in AR. Patterns of DNA methylation in CD4+ T cells correlate with AR severity, and studies show that allergic children exhibit altered methylation at CpG sites in both blood mononuclear and airway epithelial cells [103]. Sublingual immunotherapy in respiratory allergy patients is associated with decreased methylation at Foxp3 CpG sites in regulatory T cells, potentially enhancing their immunosuppressive function [104]. Additionally, the hypermethylation of DNA correlates with reduced IFN-γ expression in AR, while DNA hypomethylation may increase the mRNA expression of IL-33 and IgE, further promoting inflammation [57,105,106]. Methylation alterations within the melatonin receptor 1A gene, a paternally inherited variant, may also predispose individuals to AR [107].

3.2.2. Histone Deacetylation in AR

In parallel with DNA methylation, HDACs play a key role in the regulation of immune responses in AR. Histone modifications regulate chromatin structure and gene transcription [108]. In AR, HDAC activity increases pro-inflammatory cytokines and reduces anti-inflammatory responses. H3K9 acetylation and H3K4 trimethylation at IL4 are linked to AR [109]. Studies on AR patients have shown increased HDAC activity in immune cells, suggesting that HDAC inhibitors may help alleviate AR symptoms. Specifically, HDAC1 is upregulated in the nasal epithelial cells of AR patients and IL-4 can further increase HDAC1 expression, which disrupts nasal epithelial barrier integrity [110]. Antigen-specific immunotherapy has also been observed to downregulate HDAC1 expression in nasal mucosa while upregulating TWIK-related potassium channel-1 (TREK-1), which is typically downregulated in AR [111]. Increased HDAC1 activity may, therefore, contribute to AR by suppressing TREK1 expression, promoting pro-inflammatory cytokines, and reducing levels of anti-inflammatory cytokines, such as IL-10 and FOXP3, which are crucial for regulatory T cell function [111]. HDAC inhibitors such as trichostatin A (TSA) and sodium butyrate counteract this dysfunction in mouse models [112].

3.2.3. MicroRNAs in AR

Complementing these mechanisms, altered miRNA profiles fine-tune gene expression, adding another layer of complexity to the epigenetic regulation of AR, with some miRNAs contributing to specific disease features. Downregulation of miRNAs such as miR-21 and miR-126 in neonatal mononuclear leukocytes correlates with AR development [113], while miR-181a levels may indicate disease severity in children [114] Additionally, miR-1 downregulation by IL-13 may facilitate eosinophil migration [115]. MiR-29a is elevated in the nasal mucosa of AR patients and promotes AR progression by suppressing apoptosis in nasal epithelial cells through FOS downregulation [116]. Furthermore, upregulated miR-221, miR-19a-5p, and miR-142-3p in nasal mucosa act as AR biomarkers, promoting mast cell degranulation [117,118]. Although limited, studies on circulating miRNAs suggest their potential as biomarkers for upper airway diseases, as levels of miR-206, miR-125b, miR-126, miR-299-5p, and miR-133b have been linked to AR [88,119]. Other notable findings include the upregulation of miR-498, miR-187, miR-874, miR-143, and miR-886-3p and the downregulation of miR-18a, miR-126, let-7e, miR-155, and miR-224 in AR patients [120] (Figure 2).

4. Epigenetics in Chronic Sinusitis with Nasal Polyps (CRSwNP)

CRS is categorized into CRSwNP and CRSsNP and is a growing medical concern. It has a significant impact on patients’ quality of life and existing treatments often fall short [30]. Nasal polyps are present in approximately 2.7% of the population, with a higher prevalence in men, older adults, and individuals with asthma [33]. The pathogenesis of CRSwNP is influenced by Th2 responses and both genetic and environmental factors.

4.1. DNA Methylation in CRSwNP

Epigenetic mechanisms bridge genetic predispositions and environmental triggers in CRSwNP. Increased DNA methylation at the TSLP locus is associated with eosinophilic inflammation [30], while hypermethylation of COL18A1 may affect angiogenesis, contributing to polyp formation [121]. Eosinophil counts in nasal polyps correlate with disease severity, and the Wnt5A receptor FZD5 is elevated in eosinophilic CRSwNP. The bacterium Staphylococcus aureus, which is linked to CRSwNP, may induce the hypermethylation of genes, further contributing to inflammation [122].

Methylation of KRT19 and NR2F2 is associated with increased mRNA expression and polyp development. Furthermore, the hypermethylation of PLAT may promote fibrin deposition, while elevated IL-8 levels attract neutrophils to inflamed tissues [31]. These findings highlight how DNA methylation contributes to CRSwNP’s pathogenesis and offer potential avenues for diagnostic and therapeutic exploration.

4.2. Histone Modification in CRSwNP

Histone modifications, particularly through histone deacetylases (HDACs), also play a crucial role in CRSwNP. TSA, an HDAC inhibitor, has been shown to reduce TGF-β1-induced extracellular matrix (ECM) expression in nasal polyp tissues. TSA effectively reverses the impact of TGF-β1 by downregulating HDAC2 and HDAC4, leading to the reduced expression of pro-inflammatory cytokines such as IL-4, IL-5, and TGF-β1, which are involved in CRSwNP development. TSA’s potential therapeutic role in inhibiting nasal polyp formation is promising [31].

HDAC4 modulates allergic inflammation via the miR-206/HDAC4/cyclin D1 pathway [123] and may also be targeted by miR-20a-5p to alleviate allergic inflammation in mast cells [124].

Histone methylation regulates epithelial responses, particularly at H3K4, which is increased in nasal polyp tissues. Reduced H3K4me3 levels and associated decreases in MLL1 suggest potential therapeutic targets [125]. Additionally, the KDM2B gene interacts with the promoters of cell cycle regulators and contributes to histone modification patterns [126]. In CRSwNP, KDM2B and the transcriptional regulator Brg1 significantly decreased in the nasal mucosa. KDM2B’s role in regulating H3K4me3 suggests it may inhibit mucosal inflammation in CRSwNP [127] (Figure 2).

4.3. MicroRNAs in CRSwNP

Distinct microRNA (miRNA) profiles have been identified in CRSwNP, highlighting their role in the disease’s pathogenesis. In CRSwNP tissues, five upregulated miRNAs were identified, including miR-210-5p and miR-320a, as well as nineteen downregulated miRNAs, such as miR-32-3p and miR-548a-3p, compared to healthy controls [128]. Interestingly, studies in CRSwNP patients showed the upregulation of miR-125b and miR-155 and the downregulation of miR-92a and miR-26b compared to individuals with chronic rhinosinusitis without polyps (CRSsNP) [129].

Several individual miRNAs have been linked to specific mechanisms in CRSwNP. For example, miR-19a may inhibit IL-10 expression in dendritic cells (DCs), making it a potential target for immunotherapy [130]. MiR-125b, commonly found in eosinophilic CRSwNP, reduces the protein expression of 4E-BP1, suggesting a role in enhancing antiviral immunity [131]. Elevated levels of miR-142-3p have been associated with inflammatory responses in CRSwNP, functioning through the LPS-TLR-TNF-α signaling pathway [132]. MiR-21, which is upregulated in CRSwNP, leads to increased PTEN levels and decreased Akt phosphorylation when downregulated, indicating a possible TGF-β1–miR-21–PTEN–Akt axis in the disease process [133].

Conversely, miR-4492 is downregulated in CRSwNP tissues and correlates inversely with IL-10, suggesting its involvement in the JAK/STAT signaling pathway related to nasal polyps [134]. Additionally, DNA methylation can suppress miRNA transcription by modifying CpG islands in their promoter regions, while some miRNAs can inhibit DNA methyltransferases, impacting global methylation patterns [135]. This interplay between miRNAs and DNA methylation underscores the complexity of gene regulation in nasal polyps (Figure 1 and Figure 2).

4.4. Matrix Metalloproteinases in CRSwNP

Matrix metalloproteinases (MMPs) are key regulators in the pathogenesis of CRSwNP, playing essential roles in tissue remodeling, inflammation, and immune modulation [136]. MMP-9 has been found to be elevated in CRSwNP tissues, contributing to ECM degradation and tissue destruction [137]. Additionally, MMP-12 is significantly upregulated in nasal polyp samples, indicating its involvement in the inflammatory processes of CRSwNP [138]. These findings suggest that MMP-9 and MMP-12 are critical players in disease progression and could potentially serve as biomarkers for disease severity. Other MMPs, along with tissue inhibitors of metalloproteinases (TIMPs), modulate the balance between tissue degradation and repair, further emphasizing their therapeutic potential in CRSwNP management [136] (Figure 1 and Figure 2).

5. Links Between Atopic Dermatitis, Rhinitis, and CRSwNP

5.1. The Connection Between Periostin, IL-13, and IL-4 in AD, AR, and CRSwNP

AD, AR, and CRSwNP are characterized by a dysregulated immune response, predominantly involving Th2 cell-mediated inflammation. Periostin, a matricellular protein encoded by POSTN, is increasingly recognized as a significant biomarker and mediator in this context [139,140]. IL-4 and IL-13 are crucial in promoting the Th2 immune response, which is a hallmark of both AD and AR. These cytokines stimulate the production of IgE and enhance the recruitment of eosinophils, contributing to the inflammatory milieu observed in these diseases [141]. Specifically, IL-4 is known to induce the expression of POSTN in various cell types, including fibroblasts and keratinocytes, thereby facilitating tissue remodeling and inflammation [142]. In AD, elevated levels of IL-4 and IL-13 correlate with disease severity, as evidenced by increased POSTN levels in affected skin, possibly via the IL-13–periostin–integrin axis [140,143]. Furthermore, the expression of IL-13 in the nasal mucosa has been documented in patients with AR, particularly following allergen exposure, indicating the systemic involvement of these cytokines in allergic responses [144].

Periostin itself has been implicated in the pathogenesis of AD, AR, and CRSwNP. It is produced in response to IL-13 and is associated with eosinophilic inflammation, which is a common feature of these conditions [141]. Studies have shown that periostin levels correlate with clinical severity in AD, reinforcing its potential role as a biomarker for disease activity [143]. Additionally, it promotes chronic allergic inflammation by enhancing the responsiveness of various immune cells to Th2 cytokines, thus perpetuating the inflammatory cycle [145]. Moreover, tissue and serum periostin levels and POSTN expression appear elevated in CRSwNP, especially in eosinophilic inflammation, compared to CRSsNP and controls. Disease severity and comorbidities are also reflected in POSTN values [146]. The interplay between IL-4, IL-13, and periostin suggests a feedback loop that exacerbates the inflammatory response in both AD and AR (Figure 2).

Moreover, the therapeutic targeting of IL-4 and IL-13 has shown promise in managing these conditions. Dupilumab, an IL-4 receptor antagonist, has been effective in reducing the severity of AD and AR symptoms by inhibiting the actions of these cytokines [147]. This therapeutic approach underscores the critical role of IL-4 and IL-13 in the pathophysiology of atopic diseases and highlights the potential of periostin as a therapeutic target or biomarker for monitoring treatment response [148] (Table 1).

Table 1. Interconnected genetic and epigenetic insights into atopic dermatitis (AD), allergic rhinitis (AR), and chronic rhinosinusitis with nasal polyps (CRSwNP).

	AD	AR	CRSwNP	Refs
Type of Inflammation	Skin-localized but with a systemic Th2-driven cytokine response	Th2 inflammation in the respiratory tract driven by allergens	Nasal mucosal Th2 inflammation with eosinophilic dominance and polyp formation	[1,7,70]
Barrier Dysfunction	Impaired skin barrier due to FLG mutations and Th2	Barrier dysfunction leading to allergen sensitization	Epithelial damage with goblet cell hyperplasia and biofilm formation	[24,97,147]
Role of Periostin	Enhances skin thickening and chronic itching	Promotes airway hyperresponsiveness	Associated with fibrosis and extracellular matrix deposition	[97,148,149]
Role of the Microbiome	S. aureus exacerbates inflammation	Dysbiosis linked to IgE-mediated hypersensitivity	Biofilms (S. aureus) promote chronicity and resistance to therapies	[97,148,149]
Key Cytokines	IL-4, IL-13, IL-31	IL-4, IL-5, IL-13	IL-4, IL-5, IL-13, TGF-β	[7,121,124]
Epigenetic Mechanisms	Differential methylation and miRNAs regulating Th2 pathways	Methylation impacting IgE and IL-33 expression	Histone acetylation linked to polyp growth and eosinophilic inflammation	[36,60,69]
MicroRNAs	miR-146a miR-155, and miR-29b modulate inflammation and barrier integrity	miR-146a, miR-155 miR-125b, and miR-21 regulate airway inflammation	miR-146a, miR-155 miR-125b, and miR-21 involved in fibrosis and epithelial remodeling	[21,50,86,87,128,129,131,150]
MMP Activity	MMP-2 and MMP-9 disrupt the skin’s architecture, worsening barrier dysfunction	MMP-9 and MMP-12 contribute to airway remodeling	MMP-2, MMP-9, and MMP-12 drive polyp growth and extracellular matrix remodeling	[129,130,150,151,152,153]
Inflammasome Activation	Inflammasomes (e.g., NLRP3) amplify IL-1β and IL-18 secretion in lesions	Activated by allergens, contributing to airway inflammation	Enhanced by microbial biofilms, perpetuating chronic nasal inflammation	[138,148]
Clinical Manifestations	Chronic itch, eczema, and lichenification	Sneezing, congestion, and rhinorrhea	Nasal obstruction, hyposmia, and visible nasal polyps	[10,11,70]

The connection between periostin, IL-4, and IL-13 is integral to understanding the mechanisms underlying AD and AR. The Th2 cytokines IL-4 and IL-13 not only drive the inflammatory processes characteristic of these conditions but also regulate the expression of POSTN, which in turn contributes to tissue remodeling and chronic inflammation. This triad of interactions presents opportunities for targeted therapies aimed at mitigating the impact of these allergic disorders.

5.2. The Connection of Metalloproteinases and microRNAS in AD, AR, and CRSwNP

The connection between matrix metalloproteinases (MMPs) and microRNAs (miRNAs) in AD and AR is an emerging area of research that highlights the complex regulatory mechanisms involved in these allergic conditions. MMPs are a group of enzymes that play crucial roles in extracellular matrix remodeling and inflammation, while miRNAs are small non-coding RNAs that regulate gene expression post-transcriptionally, influencing various biological processes including inflammation and immune responses.

MMPs, particularly MMP-2 and MMP-9, have been implicated in the pathogenesis of both AD and AR. These enzymes facilitate the degradation of extracellular matrix components, which is essential for tissue remodeling and repair during inflammatory processes [149,154]. In the context of AD, MMPs contribute to the disruption of the skin barrier, leading to increased trans-epidermal water loss and susceptibility to allergens [149]. Elevated levels of MMPs have been observed in the lesional skin of AD patients, correlating with disease severity [149,154]. Similarly, in AR, MMPs are involved in the remodeling of nasal tissues, contributing to the chronic inflammation characteristic of the disease [149].

Recent studies have shown that miRNAs can modulate the expression of MMPs, thereby influencing the inflammatory response in AD and AR. Specific miRNAs have been found to downregulate MMP expression, which can lead to reduced inflammation and improved barrier function [155]. Particularly, miR-203 has been identified as a key regulator in skin diseases, including AD, where it may affect keratinocyte differentiation and proliferation, thereby influencing MMP activity and the overall inflammatory response [155]. Furthermore, dysregulation of miRNAs has been linked to the persistence and severity of allergic diseases, suggesting that they play a critical role in the pathophysiology of both AD and AR [155].

The interplay between MMPs and miRNAs is particularly relevant in the context of the “atopic march”, where early manifestations of AD can lead to the subsequent development of AR and asthma. The chronic inflammation driven by MMPs can exacerbate the dysregulation of miRNAs, creating a feedback loop that perpetuates the allergic response [156]. For example, the upregulation of MMPs in response to Th2 cytokines, such as IL-4 and IL-13, can further influence miRNA expression, leading to a sustained inflammatory state [156].

Moreover, therapeutic strategies targeting either MMPs or specific miRNAs hold promise for managing AD and AR. By modulating MMP activity or restoring normal miRNA expression profiles, it may be possible to alleviate the inflammatory responses associated with these conditions [157]. The use of miRNA mimics or inhibitors could potentially reverse the dysregulation observed in allergic diseases, providing a novel approach to treatment [155,157].

The connection between metalloproteinases and microRNAs in AD and AR can be illustrated by the intricate regulatory networks that govern inflammation and tissue remodeling in these allergic conditions. Unraveling these interactions may pave the way for innovative therapeutic strategies aimed at mitigating the impact of these diseases on affected individuals (Table 1, Figure 2).

5.3. Links Between Metalloproteinases, the Inflammasome, and Staphylococcus in AD, AR, and CRSwNP

Chronic inflammatory diseases such as AD, AR, and CRSwNP also share underlying mechanisms involving tissue remodeling and persistent inflammation. Central to these processes are the inflammasomes and MMPs, which play pivotal roles in modulating inflammation and ECM turnover. Inflammasome overactivation exacerbates Th2 inflammation via IL-1β and IL-18, while MMP9 overexpression disrupts skin barrier integrity and ECM stability [158]. Genetic predisposition enhances inflammasome activation and MMP activity in nasal tissues, driving Th2 polarization. Fungal exposure triggers NLRP3 activation, and polymorphisms amplify chronic inflammation [159]. Dysregulated MMP9 and MMP12 contribute to polyp growth and tissue remodeling, particularly in CRSwNP [151,160].

5.3.1. Genetic and Epigenetic Modifications Influencing Inflammasome Activity

NLRP3 polymorphisms and variants such as rs10754558 have been implicated in heightened inflammasome activation in AD and AR, promoting IL-1β and IL-18 release, which further enhance Th2-driven inflammation [161,162]. Similarly, variants in the Caspase-1 (CASP1) gene, particularly those affecting enzymatic activity, correlate with the increased risk and severity of CRSwNP [163]. Polymorphisms in the IL1B Gene (rs16944 and rs1143627) influence IL-1β production, exacerbating the Th2 response, especially in AD and AR. The PYCARD gene, which encodes the ASC adaptor protein essential for inflammasome assembly, also displays polymorphisms that affect its expression, particularly in CRSwNP associated with fungal pathogens [164,165] (Table 2).

Table 2. Table highlighting S. aureus’ multifaceted contributions across AD, AR, and CRSwNP.

Aspect	AD	AR	CRSwNP	Refs
Colonization	S. aureus colonizes damaged skin, particularly in barrier-deficient areas.	S. aureus can colonize nasal mucosa, increasing inflammation.	Persistent colonization in nasal polyps, often associated with biofilms.	[97,145]
Toxins and Superantigens	Produces α-toxin, β-toxin, and superantigens that trigger T-cell activation and IL-1β release via NLRP3 inflammasome activation.	Superantigens stimulate T-cell responses, amplifying type 2 inflammation.	Superantigens and toxins drive eosinophilic inflammation and Th2 polarization.	[97,146,148]
Barrier Dysfunction	Toxins disrupt keratinocyte tight junctions, worsening skin barrier integrity.	Toxins impair nasal epithelial integrity, enhancing allergen penetration.	Biofilms and toxins disrupt mucosal barriers, promoting polyp growth.	[97,147]
Inflammasome Activation	Activates the NLRP3 inflammasome in keratinocytes, leading to IL-1β and IL-18 production.	NLRP3 inflammasome activation in nasal epithelial cells amplifies inflammation.	Persistent inflammasome activation exacerbates chronic inflammation and tissue remodeling.	[136,148]
Cytokine Amplification	Promotes Th2 cytokine response (IL-4, IL-5, and IL-13) through superantigen activity.	Increases Th2 cytokines, promoting IgE-mediated hypersensitivity.	Enhances Th2 cytokine production, perpetuating eosinophilic inflammation.	[136,148,149]
Biofilm Formation	Rare in AD; typically affects acute lesions with heavy bacterial burdens.	Rarely forms; contributes to chronicity in recurrent cases.	Commonly forms in nasal polyps, fostering chronic inflammation and immune evasion.	[148,149]
Eosinophilic Recruitment	Enhances eosinophil migration via IL-5 and eotaxins, exacerbating inflammation.	Stimulates eosinophil infiltration in nasal tissues.	Eosinophil-driven inflammation is a hallmark, often worsened by biofilms.	[136,148,149]
Epigenetic Influence	Modifies DNA methylation (e.g., hypomethylation of inflammasome genes such as NLRP3).	Alters methylation patterns, enhancing pro-inflammatory gene expression.	Biofilm presence alters histone acetylation and miRNA profiles, amplifying inflammation.	[136,148,149]

SNPs in MMP genes, such as rs3918242 in MMP9 and rs243865 in MMP2, are associated with altered enzymatic activity, contributing to tissue remodeling in AD and CRSwNP. Variants in MMP12 increase elastase activity, which is linked to airway remodeling in AR and CRSwNP [151]. Imbalances in tissue inhibitors of metalloproteinases (TIMPs), regulated by genetic variants such as TIMP1 rs4898, disrupt ECM homeostasis in these conditions.

Epigenetic modifications also play a significant role. Hypermethylation of the NLRP3 promoter in AD correlates with reduced inflammasome activation during remission phases, while hypomethylation of IL1B enhancers amplifies cytokine production in AR and CRSwNP [151]. Histone acetylation, such as H3K27ac at the NLRP3 locus, increases transcriptional activity in AD and CRSwNP. Deacetylation of inflammasome repressors by HDACs exacerbates inflammation [151]. Furthermore, miRNAs such as miR-223 directly target NLRP3, and its reduced expression is linked to overactivation in CRSwNP [150]. Additionally, miR-155 promotes inflammasome signaling by stabilizing IL-1β mRNA in AD and AR, miR-29b suppresses MMP2 and MMP9 expression and its downregulation in AD, and CRSwNP facilitates excessive ECM remodeling. Finally, miR-146a modulates TIMP1 expression, impacting the MMP/TIMP balance in AR and CRSwNP [150,152,153].

5.3.2. Role of Staphylococcus aureus in Modulating Inflammasomes and Metalloproteinases

Staphylococcus aureus plays a critical role in exacerbating AD, AR, and CRSwNP through its interactions with inflammasomes and metalloproteinases [166]. The bacteria produce superantigens that activate T cells and stimulate IL-1β production by inducing NLRP3 inflammasome activation [167]. This mechanism is pivotal in AD exacerbation and is also implicated in nasal mucosa inflammation in AR. Furthermore, α- and β-toxins secreted by S. aureus damage epithelial cells, triggering damage-associated molecular pattern (DAMP) signals that activate the NLRP3 inflammasome [168] (Table 2).

S. aureus and its enterotoxins upregulate MMP9 expression in epithelial and immune cells, leading to ECM degradation and barrier dysfunction. These enterotoxins also induce NLRP3 inflammasome activation, amplifying IL-1β production and perpetuating eosinophilic inflammation [169]. This effect is particularly relevant in AD, where skin barrier impairment facilitates colonization, and in CRSwNP, where polyp formation is exacerbated [30].

Biofilms formed by S. aureus significantly contribute to CRSwNP by fostering chronic inflammation, tissue remodeling, and immune evasion. These microbial communities produce superantigens and toxins that exacerbate Th2-driven inflammation and activate epigenetic pathways, including DNA methylation and histone acetylation, enhancing inflammasome and metalloproteinase gene transcription [169,170]. Additionally, S. aureus alters miRNA profiles, notably reducing miR-223 and miR-29b expression [171]. This reduction intensifies NLRP3 activation and MMP-driven ECM degradation [172]. The bacteria also impact the MMP/TIMP balance by suppressing TIMP1 expression, aggravating tissue remodeling processes [170].

Chronic colonization with S. aureus is linked to severe phenotypes of AD. The interplay between microbial toxins, NLRP3 activation, and MMP9 overexpression perpetuates inflammation and barrier dysfunction. In CRSwP, S. aureus biofilms within nasal polyps serve as reservoirs for inflammation, amplifying inflammasome activation and metalloproteinase-driven tissue remodeling [173].

The genetic and epigenetic regulation of inflammasomes and metalloproteases underscores their integral roles in AD, AR, and CRSwNP pathophysiology. Additionally, the contribution of S. aureus in modulating these pathways highlights the complex interplay between host genetics, microbial colonization, and chronic inflammation. Targeted modulation of these pathways, through gene editing, microbiome management, or epigenetic therapies, holds promise for the development of innovative treatments for these interconnected conditions.

6. Links Between AD and CRSwNP

AD and CRSwNP are distinct conditions that often coexist within the spectrum of type 2 inflammatory diseases [57,174]. They are both characterized by chronic inflammation, barrier dysfunction, and immune dysregulation, frequently involving shared pathways such as Th2-driven cytokines, eosinophilic infiltration, and IgE sensitization [34]. This expanded discussion delves deeper into the immunological, clinical, and therapeutic interconnections between these diseases, highlighting shared mechanisms, comorbidities, and the potential for integrated management (Figure 1 and Figure 2 and Table 1 and Table 3).

Table 3. Key novel findings of this review on genetic and epigenetic interconnections between atopic dermatitis, allergic rhinitis, and rhinitis with nasal polyps.

Aspect	Novel Findings	Clinical Implications	Refs
Genetics in AD, AR, and CRSwNP	Identification of filaggrin mutations in AD, shared loci (e.g., TSLP and IL1B) linked to inflammation and barrier dysfunction	Highlights genetic predispositions contributing to systemic type 2 inflammation and guides genetic risk assessment	[2,42,136]
Epigenetics	DNA methylation at TSLP and IL1B, differential histone modifications, miRNA dysregulation (e.g., miR-155 and miR-21)	Targets for developing epigenetic biomarkers and therapies aimed at reversing aberrant gene expression	[36,60,69]
Role of the Microbiome	S. aureus biofilms drive NLRP3 inflammasome activation, elevate MMP-9, and disrupt epithelial barriers	Reinforces the need for therapies targeting biofilm-induced inflammation in CRSwNP and AD	[97,148,149]
Matrix Metalloproteinases (MMPs)	Elevated MMP-9 and MMP-12 activity linked to tissue remodeling in CRSwNP, barrier dysfunction in AD	Identify MMPs as therapeutic targets for mitigating inflammation and tissue destruction	[118,129,130]
MicroRNA Pathways	miR-29b suppression drives MMP upregulation, miR-223 regulates inflammasome activity	Opens avenues for miRNA-based therapeutic interventions to restore regulatory balance	[50,131,143]
Periostin in Disease Pathways	Elevated periostin in eosinophilic inflammation linked to disease severity in AD, AR, and CRSwNP	Supports periostin as a biomarker for disease severity and treatment response, especially for biologics	[120,121,126]
Biologic Therapies	Dupilumab efficacy in inhibiting IL-4/IL-13 pathways across conditions; emerging TSLP-targeting biologics	Demonstrates success of systemic therapies and the potential for biologic expansion to other pathways.	[127,151,155]
Inflammasome Activation	Overactivation of NLRP3 amplifies IL-1β and IL-18 secretion in AD, AR, and CRSwNP	Targets inflammasome pathways for novel anti-inflammatory treatments	[136,138,149]
Environmental Influences	Urbanization and pollution exacerbate type 2 inflammation via epigenetic alterations	Suggests environmental interventions to mitigate disease progression and enhance management strategies	[4,13,36]

6.1. Immunological Overlap and Pathophysiology

Type 2 inflammation underpins the pathogenesis of both AD and CRSwNP. In AD, skin barrier dysfunction due to mutations in FLG and other structural proteins allows allergen penetration, promoting Th2 activation and the production of IL-4, IL-5, and IL-13. These cytokines mediate IgE synthesis and eosinophil recruitment, further compromising barrier integrity and perpetuating inflammation [175,176]. Similarly, in CRSwNP, disruption of the epithelial barrier in the nasal mucosa—exacerbated by local inflammation—leads to polyp formation. Elevated levels of IL-4, IL-5, and IL-13 drive eosinophilic infiltration, tissue remodeling, and mucosal edema [177].

Emerging evidence suggests that these inflammatory pathways are not confined to localized sites but contribute to systemic immune dysregulation. The overexpression of type 2 cytokines in both diseases establishes a bidirectional relationship, where atopic sensitization in AD increases the risk of developing CRSwNP, and vice versa, through systemic eosinophilia and elevated allergic responses [178].

6.2. Shared Comorbidities and Risk Factors

Patients with AD and CRSwNP frequently present with overlapping comorbidities, including asthma, allergic rhinitis, and eosinophilic esophagitis. Allergic rhinitis, which shares a common allergic etiology with AD, is a known risk factor for CRSwNP and serves as a bridging condition in this spectrum. Studies have shown that asthma exacerbates CRSwNP severity, with atopic patients often exhibiting more extensive sinus involvement and poorer outcomes [179]. The coexistence of these conditions reflects a systemic type 2 inflammatory endotype rather than isolated organ-specific diseases.

A population-based cohort study in Finland identified a significantly increased prevalence of nasal polyps and asthma in adults with AD, further supporting the notion of shared pathogenic pathways [178]. Moreover, chronic exposure to environmental allergens and microbial colonization, especially with Staphylococcus aureus, has been implicated in exacerbating both AD and CRSwNP through IgE-mediated immune responses and superantigen production [180].

6.3. Therapeutic Advances: Biologic Agents and Integrated Management

Biologic therapies targeting key mediators of type 2 inflammation, such as IL-4, IL-5, and IL-13, have revolutionized the treatment landscape for AD and CRSwNP. Dupilumab, an IL-4 receptor antagonist, has demonstrated robust efficacy in treating both conditions, leading to improvements in skin symptoms, nasal polyp burden, and associated comorbidities such as asthma [181,182]. By restoring barrier function and reducing eosinophilic inflammation, dupilumab provides a systemic solution to these interconnected diseases [181]. Other targeted therapies including anti-IgE monoclonal antibodies (omalizumab) are being explored for their potential to mitigate allergic inflammation in AD patients with concomitant AR [102,183].

However, despite its benefits, dupilumab and other biologics are not without challenges. Treatment-emergent eosinophilia, reported in a subset of patients, underscores the need for personalized approaches to therapy and vigilant monitoring of adverse effects [184]. Novel biologics, including tezepelumab, which targets TSLP, are under investigation for their potential to address unmet needs in patients with severe or refractory disease [175].

6.4. Quality of Life and Unmet Needs

Chronic symptoms associated with AD and CRSwNP, including pruritus, sleep disruption, nasal obstruction, and anosmia, significantly impair quality of life. Patients with multiple type 2 inflammatory diseases face compounded challenges, such as increased healthcare utilization, treatment burden, and psychological stress [185]. Addressing these issues requires a holistic, patient-centered approach that considers not only disease control but also psychosocial and functional outcomes.

In recent years, the concept of “remission” in type 2 inflammatory diseases has gained traction, emphasizing sustained symptom control and improved quality of life as therapeutic goals [186]. Multidisciplinary care involving dermatologists, allergists, and otolaryngologists is essential for optimizing outcomes in patients with overlapping AD and CRSwNP.

7. Conclusions and Key Novel Findings

The interplay between AD, AR, and CRSwNP exemplifies the systemic nature of type 2 inflammation and highlights the importance of recognizing these diseases as part of a unified spectrum. This review provides novel insights into the interconnected molecular and clinical pathways that link AD, AR, and CRSwNP. Shared and distinct genetic, epigenetic, and molecular mechanisms characterize these conditions with Th2-driven inflammation mediated by IL-4, IL-5, and IL-13, along with dysregulation of MMPs and miRNAs, highlighting the systemic nature of these conditions. Periostin emerges as a key mediator across all diseases, contributing to skin thickening in AD, airway hyper-responsiveness in AR, and fibrosis in CRSwNP. Barrier dysfunction also plays a central role, although through distinct mechanisms. FLG mutations and Th2 cytokines disrupt the skin barrier in AD, while epithelial damage and goblet cell hyperplasia exacerbate inflammation in AR and CRSwNP.

Novel findings (Table 3), including the role of epigenetic modifications as critical drivers with unique DNA methylation patterns at loci such as TSLP and IL1B in CRSwNP, combined with the identification of novel filaggrin mutations in AD, underline the impact of genetic predispositions on disease progression. Additionally, differential microRNA expression, including miR-155 and miR-146a, provides new perspectives on post-transcriptional regulation of inflammation across all three conditions. Furthermore, disease-specific miRNAs such as miR-125b and miR-21 in AR and CRSwNP influence airway remodeling.

Microbial dysbiosis, particularly the role of Staphylococcus aureus, is another unifying factor in sustaining chronic inflammation and driving epigenetic modifications, particularly in CRSwNP. The influence of biofilms formed by S. aureus on inflammasome activation and MMP activity in CRSwNP reinforces the importance of targeting microbial contributions in therapeutic strategies (Table 2).

Matrix metalloproteinases, such as MMP-2, MMP-9, and MMP-12, play critical roles in tissue remodeling and inflammation, particularly in CRSwNP. The differential impact of histone acetylation and matrix remodeling enzymes, including MMP-9 and MMP-12, further distinguishes polyp formation in CRSwNP from skin barrier dysfunction in AD. The cytokine milieu also diverges, with TGF-β uniquely implicated in CRSwNP fibrosis while IL-13-driven epithelial barrier disruption is prominent in AD and AR (Table 1).

This study highlights both shared and divergent features of these conditions, offering avenues for innovative therapeutic approaches. Advances in biologics such as dupilumab, which targets IL-4 and IL-13 pathways, demonstrate promise in addressing overlapping pathways, while emerging strategies, including miRNA modulation and MMP inhibitors, hold potential for targeted interventions. By deepening the understanding of these molecular mechanisms, this work paves the way for the personalized and integrative management of type 2 inflammatory diseases.

Despite recent progress, significant challenges remain. The heterogeneity of disease phenotypes, variable therapeutic responses, and gaps in our understanding of the epigenetic–microbiome interplay highlight the need for further investigation. Future research should focus on elucidating the molecular crosstalk between skin and mucosal barriers and identifying biomarkers for disease prediction and therapeutic responses to enhance efficacy and safety. The development of multi-target biologics and combination therapies holds promise for addressing the overlapping pathways in these interconnected conditions. Furthermore, leveraging advanced technologies, such as transcriptomics, exposomics, single-cell sequencing, and CRISPR-based gene editing, can deepen our insights into the molecular mechanisms driving these diseases [21,187].

Bridging molecular insights with clinical innovations and a multidisciplinary approach spanning dermatology, immunology, and otolaryngology, future research has the potential to redefine disease trajectories, offering sustained symptom control and improved outcomes for patients across this spectrum of type 2 inflammatory diseases. This integrated framework has the potential to transform patients affected by this complex inflammatory network and redefine our understanding of atopic conditions in the years to come.