The role of type 2 inflammation in the pathogenesis of atopic dermatitis

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Abstract

Relevance. Atopic dermatitis (AD) is classified as a chronic immune-­mediated disease, with its pathogenesis rooted in genetic predisposition and immune response dysregulation, predominantly driven by T2‑inflammatory reactions. This review highlights key aspects of the immunopathogenesis of AD, emphasizing its systemic inflammatory nature linked to T2‑immune dysregulation. This leads to the activation of cytokines such as IL‑4, IL‑5, IL‑13, and IL‑31. The article analyzes modern treatment approaches, including targeted therapy aimed at blocking T2 cytokines, stressing the importance of early intervention to prevent complications and the development of the atopic march. Understanding T2‑inflammation mechanisms opens new opportunities for developing effective personalized therapies for AD. Conclusion. Type 2 inflammation plays a pivotal role in the pathogenesis of AD, driving chronic inflammation, skin barrier dysfunction, and the clinical manifestations of the disease. Key mediators of T2 inflammation-­including IL‑4, IL‑5, IL‑13, and IL‑31‑regulate the activation of various immune-­competent cells, not only amplifying inflammation but also contributing to the development of pruritus. This, in turn, establishes the self-perpetuating “itch-scratch” cycle, which exacerbates skin damage and further stimulates inflammatory processes. Impaired skin barrier function also facilitates the penetration of allergens and microbial agents, further activating the immune response and worsening disease severity. Studying type 2 inflammation as a central mechanism in AD pathogenesis not only advances our understanding of the disease but also facilitates the development of new therapeutic strategies to control AD and improve patients’ quality of life, which remains a priority in contemporary immunology, allergology, and dermatology.

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Introduction

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by genetic predisposition, epidermal barrier dysfunction, and dysregulated type 2 immune responses [1, 2]. Immune-­mediated inflammatory diseases are classified into three main types based on the predominant immune response driving their pathogenesis.

Type 1 inflammatory diseases are associated with excessive activation of Th1 lymphocytes and innate immune cells, leading to increased production of cytokines such as interferon-γ (IFN-γ), interleukin (IL)-12, and tumor necrosis factor (TNF). These cytokines provide protection against intracellular pathogens, but their overproduction triggers chronic inflammation and tissue damage. Examples of such diseases include rheumatoid arthritis, sarcoidosis, and Crohn’s disease.

Type 2 inflammatory diseases are characterized by the predominance of Th2 lymphocytes, type 2 innate lymphoid cells (ILC2s), and cytokines such as IL‑4, IL‑5, and IL‑13, which are associated with allergic inflammation, eosinophil activation, IgE production, and impaired skin and mucosal barrier function. Examples include AD, asthma, allergic rhinitis (AR), and related conditions.

Type 3 inflammatory diseases are driven by Th17 cell activation and the production of IL‑17 and IL‑22, which promote neutrophilic inflammation. This immune response targets extracellular bacteria and fungi, but when dysregulated, it contributes to tissue damage and chronic inflammation in diseases such as psoriasis, ankylosing spondylitis, and ulcerative colitis [3, 4]. This classification of chronic immune-­mediated inflammatory diseases has become particularly relevant with the advent of targeted therapies directed at specific biological pathways.

According to global epidemiological studies, the prevalence of AD is 15–20% in children and up to 10% in adults [5]. One in five children with AD shows no detectable allergen-­specific IgE to food or airborne allergens [6]. In 20–40% of patients, AD manifests as moderate-to-severe disease and is considered a systemic disorder with multi-­organ involvement [7–9]. The pathogenesis of AD involves genetic predisposition, impaired epidermal barrier function, predominant type 2 immune responses, skin microbiome alterations, IgE-mediated sensitization to allergens, and autoimmune mechanisms, which collectively determine the disease phenotype and endotype [10].

The immune response in AD involves various immune cells, including T lymphocytes, dendritic cells, ILC2s, keratinocytes, monocytes, and eosinophils. These cells are activated by allergens and microbial agents penetrating the compromised skin barrier and produce pro-inflammatory cytokines such as IL‑4, IL‑5, IL‑13, IL‑31, and others.

Investigation of the immunological mechanisms underlying AD has become particularly crucial with the emergence of novel targeted biologic therapies. This review synthesizes current understanding of type 2 inflammation in AD pathogenesis and evaluates contemporary therapeutic approaches for disease management.

Key characteristics of type 2 inflammation

The type 2 immune response normally provides protection against parasitic and helminthic invasions and supports the barrier functions of the skin and mucous membranes. However, its dysregulation can lead to the development of type 2 inflammation. This type of immune response is characterized by the activation of Th2 cells, ILC2s, and an increased production of cytokines such as IL‑4, IL‑5, IL‑9, IL‑10, IL‑13, IL‑31, certain chemokines, as well as IL‑25, IL‑33, and thymic stromal lymphopoietin (TSLP), which are mainly secreted by non-immune cells. The main biological functions of these cytokines are presented in Table 1 [3, 11].

Table 1
The main biological functions of T2 cytokines

 Cytokine/ References

 Main biological functions

 IL‑4/ [11–13]

 Stimulation of Th2 cell differentiation.Maintenance of survival, long-term persistence, and activity of Th2 cells under inflammatory conditions.Regulation of antibody production: stimulation of B cell isotype switching from IgM to IgE; enhancement of IgG4 production.Stimulation of eosinophils via activation of IL‑5 and other mediators.Epidermal barrier dysfunction: downregulation of structural barrier proteins (filaggrin, involucrin, loricrin).Impaired antimicrobial defense: reduced synthesis of skin lipids and antimicrobial peptides.Modulation of inflammation through activation of other immune cells, including mast cells, basophils, and macrophages, and maintenance of pro-inflammatory cytokine production (IL‑13).Tissue remodeling via stimulation AAMs, which participate in tissue repair and remodeling.

 IL‑13/ [11–13]

 Stimulation of the production of other Th2 cytokines: IL‑4 and IL‑5.Maintenance of eosinophilic inflammation through interactions with other cytokines, including IL‑5.Activation of AAMs, supporting chronic inflammation.Epidermal barrier dysfunction: downregulation of structural barrier proteins (filaggrin, involucrin, loricrin).Impaired antimicrobial defense: reduced synthesis of skin lipids and antimicrobial peptides (cathelicidins and beta-defensins).Enhancement of collagen and polyamine synthesis, contributing to tissue remodeling and repair.Goblet cell hyperplasia and increased mucus production, especially in the airways.Activation of sensory neurons, amplifying itch perception and pruritogenic responses.Stimulation of B cells isotype switching to IgE, thereby intensifying allergic reactions.

 IL‑5/ [11, 14]

 Regulation of eosinophils: stimulation of proliferation, maturation, and survival of eosinophils in the bone marrow; enhancement of eosinophil migration from the bloodstream to inflamed tissues.Activation of eosinophils: increased capacity of eosinophils to secrete granule contents (major basic protein, peroxidase, etc.) for the destruction of parasites and pathogens.Increased accumulation of eosinophils at sites of inflammation, contributing to the chronicity of inflammatory processes, especially in allergic diseases.Interaction with other Th2 cytokines (IL‑4, IL‑13), supporting allergic inflammation.Participation in the elimination of large extracellular pathogens, such as helminths, through activation of eosinophils and basophils.Maintenance of basophil survival, their activation, and migration into tissues.Induction of angiogenesis: stimulation of new blood vessel growth, which is associated with the maintenance of inflammatory processes

 IL‑31/ [15, 16]

 Pruritogenic function: activation of sensory neurons via IL‑31 receptor alpha (IL‑31RA) and oncostatin M-specific receptor beta (OSMRβ); IL‑31 is a key mediator of itch in AD, chronic nodular prurigo, and other inflammatory skin diseases.Epidermal barrier dysfunction: downregulation of structural barrier proteins (filaggrin, involucrin, loricrin).Stimulation of keratinocytes to produce pro-inflammatory cytokines and chemokines CCL17 and CCL22.Amplification of skin inflammation by recruiting additional immune cells, including eosinophils and Th2 cells.Tissue remodeling: stimulation of cell proliferation and growth factor production.Interaction with other type 2 inflammation mediators IL‑4 and IL‑13.Involvement in itch mechanisms in systemic diseases such as Hodgkin lymphoma.Influence on the skin microbiome, creating conditions favorable for the growth of pathogenic microorganisms like Staphylococcus aureus.Interaction of IL‑31 with skin and immune cells contributes to the transition from acute to chronic inflammation.

 IL‑9/[17]

 Proliferation, survival, and activation of mast cells, promoting the release of histamine and other mediators.Maintenance of type 2 inflammation: stimulation of IL‑4 and IL‑13 production.Participation in the immune response against helminths by stimulating mast cells, mucus secretion, and recruitment of immune cells to affected tissues.Stimulation of eosinophils.Enhancement of mucus secretion in the airways, contributing to parasite clearance but also causing hypersecretion in bronchial asthma.Stimulation of fibroblasts to produce collagen, potentially contributing to tissue fibrosis in chronic inflammation.Activation of ILC2s, which produce type 2 cytokines.Stimulation of B cells isotype switching to IgE, thereby intensifying allergic reactions.

 IL‑10/[18–20]

 Suppression of inflammation: inhibition of the production of pro-inflammatory cytokines IL‑1, IL‑6, IL‑12, IFN-γ, and TNF-α.Reduction of macrophage and dendritic cell activation by suppressing their antigen-­presenting capacity and release of pro-inflammatory mediators.Inhibition of activation and proliferation of Th1 cells, thereby limiting inflammation.Maintenance of survival and function of Tregs, which play a critical role in preventing autoimmune diseases.Stimulation of antibody production by B cells, especially IgG4 and Ig A.Decreased production of autoantibodies, which is important for preventing the development of autoimmune reactions.Limitation of the inflammatory activity of neutrophils and macrophages.Reduction in the production of reactive oxygen species and enzymes capable of causing oxidative stress.Stimulation of growth factor production that supports tissue repair.Maintenance of immune tolerance: prevents hyperactivation of the immune system, ensuring tolerance to self-antigens and promoting tolerance to commensal microbes in the gut and other barrier tissues.Regulation of the microbiome.Limitation of tissue damage during infections by reducing the intensity of the inflammatory response; however, excessive IL‑10 production may weaken immune defense and contribute to infection chronicity.

 IL‑33/[16, 21]

 Activation of ILC2: IL‑33 stimulates ILC2 to produce key type 2 cytokines IL‑5 and IL‑13.Enhancement of Th2 cells differentiation and increased production of IL‑4, IL‑5, and IL‑13, contributing to the development of allergic reactions.Activation of mast cells, basophils, and eosinophils, and recruitment of immune cells to sites of inflammation.Maintenance of skin itch through activation of keratinocytes and impairment of barrier function, facilitating allergen penetration.Stimulation of macrophage and fibroblast activation, promoting tissue remodeling and repair after injury.Support of immune responses against helminths by enhancing mucus secretion and recruiting immune cells.Alarmin function: released upon tissue damage to trigger inflammatory responses.Increased vascular permeability.Influence on the microbiome composition, promoting growth of pathogenic microorganisms and thereby exacerbating inflammation.

 IL‑25/ [21, 22]

 Stimulation of differentiation and activation of Th2 lymphocytes and activation of ILC2s, which enhances the production of cytokines IL‑4, IL‑5, and IL‑13.Enhancement of eosinophil migration and activation.Participation in immune defense against helminths by stimulating mucus production, recruiting immune cells to affected tissues, and promoting intestinal smooth muscle contraction, thereby facilitating parasite expulsion.Activation of dendritic cells and macrophages, which sustain the inflammatory response.Increased production of chemokines that attract additional immune cells to the site of inflammation, further amplifying the immune response.Supports epithelial repair after injury.Maintains a type 2 immune response while suppressing Th1 and Th17 responses, thus limiting inflammation associated with other immune pathways.Interacts synergistically with other alarmins such as IL‑33 and TSLP, creating a potent signal for the activation of type 2 inflammation.

 TSLP/ [23, 24]

 Activation of dendritic cells, promoting their migration and enhancing their antigen-­presenting capacity; programs dendritic cells to stimulate Th2 lymphocyte differentiation, thereby amplifying the type 2 immune response.Stimulation of Th2 cells to produce IL‑4, IL‑5, and IL‑13, which intensify the inflammatory process.Activation of ILC2.Induction of itch and skin inflammation through activation of sensory neurons, contributing to increased pruritus, especially in AD.Enhancement and maintenance of chronic skin inflammation.Regulation of barrier functions of the skin and mucous membranes.Stimulation of migration and activation of eosinophils, mast cells, and basophils.Maintenance of survival and activation of Th2 lymphocytes.Interaction with other alarmins such as IL‑33 and IL‑25, enhancing their effects and promoting robust activation of type 2 inflammation.Modulation of interactions between immune and nervous system cells, strengthening the link between inflammation and itch.

The functions of IL‑4 and IL‑13 are largely similar but not identical: IL‑4 and, to a lesser extent, IL‑13 regulates immune response switching and IgE synthesis by plasma cells. IL‑4, but not IL‑13, promotes differentiation of T-helper cells from Th0 to Th2 cells. They also recruit inflammatory effector cells, reduce expression of filaggrin and other skin structural proteins; in mouse models these cytokines increased S. aureus skin colonization. IL‑4 and IL‑13 play a key role in macrophage activation through interaction with the IL‑4Rα receptor, which is a common receptor chain for both cytokines. This process leads to the formation of alternatively activated macrophages (AAMs), which differ from classically activated macrophages by their role in inflammation regulation, tissue repair, and parasite defense [13, 25]. Several studies have shown that IL‑4 and IL‑13 stimulate macrophages to produce mediators such as arginase‑1 (Arg1) and Resistin-like molecule α (RELMα) [26, 27]. Arg1 competes with nitric oxide synthase (iNOS) for the common substrate arginine and suppresses NO-mediated antimicrobial pathways in classically activated macrophages. A key function of Arg1 is inflammation suppression, achieved not only through iNOS inhibition but also via direct effects on T-cell function. T-cells are sensitive to arginine concentration, and its depletion through arginase activation impairs their function. Ornithine, in turn, is used for polyamine and proline synthesis, which support cell proliferation and collagen production. These processes may underlie fibrosis development and pathological tissue remodeling in asthma [28]. Furthermore, studies demonstrate Arg1’s ability to participate in tissue repair via L-ornithine and exert effector activity against nematodes by limiting parasite mobility and promoting macrophage uptake [29]. Macrophages also secrete RELMα, which can disrupt parasite metabolism and reduce their motility [30]. Macrophage activation through the IL‑4Rα receptor, shared by IL‑4 and IL‑13 cytokines, leads to their alternative activation, significantly enhancing their ability to interact with antibody-­coated parasites. This process involves several key mechanisms: increased Fc receptor expression, improved adhesion and interaction, and secretion of Arg1 and polyamines. Through IL‑4Rα activation, macrophages alter their metabolism, switching to aerobic glycolysis, which enhances their capacity for active uptake and processing of opsonized particles. Thus, IL‑4Rα-mediated macrophage activation makes them more efficient at recognizing antibody-­coated parasites, enhancing their phagocytic capacity and providing significant immune defense against parasitic infections. AAMs also participate in recruiting other immune cells, such as eosinophils, which contribute to parasite destruction through toxic granule proteins. A key biological function of IL‑4 is stimulating naive T-lymphocytes (Th0) and their differentiation into Th2 cells [3]. IL‑4 and IL‑13 promote immunoglobulin class switching in B-lymphocytes [31] and enhance IgE production [11]. One of the most important functions of IL‑4 and IL‑13 is their ability to activate sensory neurons (itch receptors) in the skin and participate in the pathological “itch-scratch” cycle, which on one hand aims to eliminate pathogens from the skin surface, but on the other exacerbates skin damage and inflammation [32, 33].

IL‑5 plays a key role in eosinophil activation, mobilization, and parasite-­killing capacity. This process involves several stages ensuring effective parasite elimination and inflammatory response regulation. IL‑5 stimulates eosinophil differentiation and maturation in bone marrow, acting on eosinophil precursors through the IL‑5 receptor (IL‑5R), enhancing their proliferation, and after cell maturation, promotes eosinophil release from bone marrow into bloodstream and migration to inflammation sites [11, 14, 34, 35]. IL‑5 increases adhesion molecule expression on eosinophils, enabling their interaction with endothelial cells and tissue migration through vascular walls [34]. IL‑5 activates eosinophils, enhancing their ability to release toxic granules upon parasite contact.

IL‑9 is an important cytokine in Th2 response, supporting mast cell, basophil and eosinophil activation. It enhances IL‑4, IL‑5 and IL‑13 production, promoting development and maintenance of allergic inflammation. IL‑9 plays a key role in parasite defense by stimulating mucus secretion and recruiting immune cells to affected tissues [36]. IL‑9 participates in both protective mechanisms and pathological processes associated with allergic diseases and chronic inflammation [37].

IL‑10 plays a crucial role in immune response regulation and homeostasis maintenance. On one hand, IL‑10 suppresses proinflammatory cytokine production (IL‑1, IL‑6, IL‑12, TNF-α, IFN-γ) by acting on macrophages, dendritic cells and other innate immune effector cells [19, 38, 39]. IL‑10 reduces antigen presentation and inflammatory mediator release by macrophages and dendritic cells, limiting excessive inflammation and protecting tissues from damage [40]. On the other hand, IL‑10 supports regulatory T-cells (Tregs), enhancing their role in suppressing inflammatory responses and preventing autoimmune reactions [41]. IL‑10 stimulates antibody production by B-cells, particularly IgA, important for maintaining mucosal barrier function in gut and airways [42]. Moreover, IL‑10 plays a key role in establishing immune tolerance to commensal microbiota, preventing excessive inflammation in barrier tissues [43]. Thus, IL‑10 has multifunctional roles, restraining inflammation and protecting against autoimmune reactions, but under certain conditions may weaken pathogen defense.

IL‑31 is a key mediator of skin itching, inflammation and tissue remodeling. It activates sensory neurons causing itch, enhances skin inflammation through keratinocyte activation and proinflammatory cytokine production [44], and impairs skin barrier function by reducing expression of key structural proteins including filaggrin [45].

Alarmins (IL‑25, IL‑33 and TSLP)

Damaged epithelial cells release alarmins that play an important role in activating innate immunity and signaling threats to the body. Their function is to rapidly recruit immune cells to sites of injury and infection.

IL‑25 plays a key role in activating type 2 inflammation by stimulating production of IL‑4, IL‑5 and IL‑13 by Th2 cells and ILC2s [46]. Studies show elevated levels of this cytokine in patients with AD and asthma [47]. IL‑25 also enhances protection against parasites and amplifies allergic inflammation by increasing migration and activation of immune cells [48]. IL‑33 is a key mediator of type 2 inflammation that activates ILC2s, basophils and mast cells, boosting production of IL‑5 and IL‑13. It plays an important role in development of asthma and AD, where its levels are elevated in affected tissues [49]. IL‑33 receptors are found on memory Th2 cells, suggesting its role in activating adaptive immune responses [50]. IL‑33 is also involved in tissue remodeling processes and exacerbates chronic inflammation, particularly in allergic and inflammatory diseases. TSLP plays a crucial role in initiating and maintaining type 2 inflammation. It activates dendritic cells which stimulate Th2 cell differentiation and production of IL‑4, IL‑5 and IL‑13 [51, 52]. TSLP also enhances inflammatory responses through OX40 ligand expression, increasing activity of Th2 cells and ILC2s [53]. Its elevated expression in skin correlates with severity of AD and induces itching by acting on sensory neurons [54].

Thus, type 2 inflammation plays an important biological role in protecting against infections including parasitic infections and maintaining skin and mucosal barrier functions. Type 2 inflammation is characterized by activation of Th2 lymphocytes, ILCs and production of key cytokines including IL‑4, IL‑5, IL‑13 and IL‑31. These cytokines regulate eosinophils, mast cells and basophils which secrete inflammatory mediators and toxic proteins to eliminate parasites. Type 2 inflammation also activates IgE production. However, beyond its protective role, type 2 inflammation contributes to pathogenesis of chronic inflammatory and allergic diseases. It disrupts skin and mucosal barriers by suppressing structural protein synthesis and increasing permeability to allergens, pathogens and nonspecific irritants. Simultaneously, type 2 inflammation maintains chronic inflammation by recruiting immune cells to affected tissues, stimulating mucus secretion and provoking itch through activation of sensory neurons by alarmins IL‑31 and TSLP. Interaction with microbiome further exacerbates inflammation, creating favorable conditions for growth of pathogenic microorganisms like S. aureus. Mechanisms of type 2 inflammation are involved in pathophysiology of multiple diseases: AD, prurigo nodularis, chronic spontaneous urticaria, bullous pemphigoid, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, asthma, and eosinophilic chronic obstructive pulmonary disease [11, 55–57].

Pathogenetic mechanisms of atopic dermatitis

AD is a common chronic type 2 inflammatory systemic disease characterized by a chronic relapsing course, based on genetic predisposition to allergy, immune dysregulation, and skin barrier dysfunction [1, 10, 58].

Impairment of skin barrier function

Disruption of the epidermal barrier is a key link in AD pathogenesis, determining both predisposition to the disease and clinical features. These changes lead to increased skin permeability to various antigens and nonspecific irritants and elevated transepidermal water loss. The main aspects of epidermal barrier dysfunction involve defects in epidermal structural proteins (filaggrin, involucrin, loricrin) [59, 60], changes in skin lipid layer composition (reduced ceramides, free fatty acids, and cholesterol) [61], increased transepidermal water loss, and decreased synthesis of antimicrobial peptides [62].

Filaggrin, the most important structural skin protein responsible for keratinization, hydration, and antimicrobial defense, is the main component of keratohyalin granules [63, 64]. Filaggrin deficiency caused by genetic disorders can lead to development of AD in early childhood, severe disease course, higher likelihood of concomitant respiratory allergic diseases, and predisposition to recurrent microbial and viral skin infections [65]. However, approximately 40% of filaggrin gene mutation carriers do not develop AD, and filaggrin mutations are found in only 15–50% of AD patients [64]. In a recently published study by Sahlén P. et al., the influence of single nucleotide polymorphisms (SNPs) identified through genome-wide association studies (GWAS) on epidermal barrier dysfunction was investigated using chromosome conformation capture [66]. It was shown that many GWAS-identified SNPs can affect distant genes, with only 35% of target genes being closest to known GWAS variants. In a GWAS-based study by DeVore et al., caspase recruitment domain family member 14 (CARD14) was shown to regulate filaggrin expression in the skin of children with AD [67], with CARD14 regulating filaggrin homeostasis depending on the rs11652075 variant in the CARD14 gene, which is also associated with psoriasis. Genetic filaggrin abnormalities do not explain all skin barrier dysfunctions in AD, but patients without such genetic defects may later show secondarily reduced filaggrin levels [68]. AD also features decreased levels of other terminal differentiation proteins of keratinocytes, such as loricrin and involucrin [69], as well as tight junction proteins [70].

AD patients also show reduced ceramide levels in both affected and unaffected skin, as well as disturbances in ceramide-to-cholesterol ratios [71]. The stratum corneum of AD patients shows elevated pH levels, leading to increased serine protease activity and contributing to inactivation and degradation of acid sphingomyelinase and glucocerebrosidase enzymes necessary for ceramide synthesis. Increased serine protease activity reduces lamellar body secretion through the protease-­activated receptor 2 (PAR2) signaling pathway, leading to decreased stratum corneum thickness in AD patients.

Activation of type 2 inflammation

AD features dysregulation of type 2 immune response, leading to development of local and systemic inflammation characterized by activation and proliferation of Th2 lymphocytes, ILCs) and involvement of proinflammatory type 2 cytokines — IL‑4, IL‑5, IL‑13 in response to allergens penetrating the impaired epidermal barrier [3, 4] (Figure). Although many immune signaling pathways involved in AD pathogenesis may underlie different disease subtypes, activation of type 2‑mediated immune mechanisms is the dominant mechanism in disease pathogenesis [1, 72, 73].

Type 2 inflammation activation is a multi-­stage process beginning with epidermal barrier damage, which can be caused by genetic defects such as filaggrin gene mutations [60, 71, 74], or external factors such as allergens [75], environmental pollution [76], and microbial toxins [77]. In response, skin epithelial cells release alarmins, including TSLP, IL‑25 and IL‑33, which activate innate and adaptive immune mechanisms. A recently published systematic review and meta-analysis included original articles examining TSLP levels in serum of AD patients [52]. The meta-analysis included 14 studies with 1032 AD patients and 416 controls. It showed that TSLP levels were significantly higher in AD patients compared to controls, with stratification by region, age, disease severity, TSLP detection method, sample size and study quality revealing significantly increased TSLP levels in adult AD patients living in Europe. TSLP elevation was found at all severity levels compared to controls, with higher levels in adults than children, and increasing with disease severity. The biological role of alarmins is described in Table 1, importantly, they play a key role in initiating type 2 inflammation by activating ILC2, mast cells, basophils and dendritic cells. TSLP-stimulated dendritic cells migrate to lymph nodes where they activate naive T cells and stimulate their differentiation into Th2 cells. These Th2 cells secrete key type 2 inflammation cytokines such as IL‑4, IL‑5, IL‑13 and IL‑31. IL‑4 and IL‑13 stimulate antibody isotype switching to IgE by plasma cells, maintaining allergic sensitization. Additionally, IL‑4 plays a key role in differentiation of Th0 cells into Th2 cells, enhancing type 2 immune response (Figure).

Fig. The main pathogenetic mechanisms of T2 inflammation in AD

IL‑4 and IL‑13 suppress synthesis of epidermal structural proteins such as filaggrin, involucrin and loricrin, which impairs skin barrier function and promotes colonization by pathogenic microorganisms such as S. aureus. IL‑5 stimulates recruitment and activation of eosinophils, which release cytotoxic granules that damage tissues and enhance inflammation. IL‑31 acts on sensory neurons, causing itch that contributes to the “itch-scratch” cycle [44]. This cycle exacerbates mechanical skin damage, worsens inflammation and maintains the chronic nature of the disease. Subsequently, inflammation may transition to a chronic phase when Th1- and Th17‑mediated immune responses join type 2 inflammation. These mechanisms contribute to tissue remodeling, epidermal thickening and increased inflammation, making AD course more severe.

Relationship between inflammation and skin microbiome disruption

Microbial factors such as S. aureus toxins and superantigens further stimulate immune response by increasing proinflammatory cytokine production and exacerbating barrier dysfunction. The skin microbiome state depends on severity of epidermal barrier impairment, climatic factors, hygiene product use, and topical therapy. In AD patients, S. aureus colonization is particularly significant as it not only triggers exacerbations but also maintains pathological immune response. S. aureus attaches to corneocytes by binding to the N-terminal region of corneodesmosin [78], and also forms biofilms closely associated with AD severity [79]. S. aureus has been shown to not only be an exacerbation factor and cause of secondary bacterial infections, but also to initiate immediate hypersensitivity-type immune responses [80–82]. Moreover, S. aureus exacerbates epidermal barrier dysfunction in AD and stimulates expression of proinflammatory cytokines [83, 84]. AD features reduced skin microbiome diversity due to staphylococcal dominance, with S. aureus contamination being significantly higher in affected versus unaffected skin areas [84, 85]. A prospective skin microbiome study assessing relationship between skin microbiota and disease progression in children aged 2–15 years with AD at different disease stages showed decreased microbiome diversity during exacerbations [86]. With impaired epidermal barrier, S. aureus can penetrate deep skin layers where it may interact with immune cells and stimulate production of type 2 cytokines: IL‑4, IL‑13 and IL‑22 and TSLP.

Not only skin microbiome but also respiratory and gastrointestinal microbiomes may play roles in AD pathogenesis. In a prospective cohort study by Lehtimäki J. et al. [87] involving 700 children from urban and rural areas, respiratory and gut microbiota were studied for potential associations with asthma and AD development. Risk of asthma and IgE sensitization to respiratory allergens was higher in urban-­reared children, with respiratory and gut microbiota composition differing between urban and rural infants.

AD patients also show increased susceptibility to fungal infections caused by Candida and  spp. TLR2 receptors play an important role in this process by mediating interaction between immunogenic proteins and keratinocytes, stimulating production of antimicrobial peptides α- and β-defensins and chemokine CXCL8. Additionally, Malassezia antigens can induce specific IgE production through T cell-mediated B cell activation [88].

Thus, type 2 inflammation activation in AD represents a complex interaction between innate and adaptive immune mechanisms, epithelial cells, nervous system and microbial factors. This interaction underlies AD clinical manifestations including itch, chronic inflammation, skin barrier dysfunction and increased allergen sensitivity. Understanding these processes opens possibilities for targeted therapy aimed at blocking key type 2 inflammation cytokines such as IL‑4, IL‑13 and IL‑31, as well as restoring skin barrier function.

Therapeutic approaches to control type 2 inflammation

Early intervention aimed at reducing the impact of systemic type 2 inflammation in AD may not only achieve disease control or remission but also reduce the likelihood of developing atopic march, i. e., the addition of comorbid allergic diseases such as asthma, allergic rhinitis, food allergies, as well as normalize skin structural changes and alter disease course [89]. The main goals of AD therapy are inflammation control, prevention of exacerbations, and improvement of patient quality of life. AD treatment depends on disease severity but always includes the use of emollients, identification and elimination of allergens and triggers. For mild cases, low-potency topical corticosteroids or calcineurin inhibitors are used, along with antihistamines to reduce itching. For moderate cases, moderate or high-potency corticosteroids are applied, with antibacterial agents prescribed when necessary to treat secondary infection. For severe AD, systemic therapy is prescribed: cyclosporine, methotrexate or targeted biologics, such as dupilumab, which blocks key type 2 inflammation cytokines IL‑4 and IL‑13, or selective JAK inhibitors (abrocitinib, baricitinib, upadacitinib) [2, 57].

Anti-cytokine targeted therapy for AD

Targeted immunotherapy for AD is aimed at specifically affecting key molecules and signaling pathways involved in inflammation development and pathological immune response in this disease. Unlike traditional systemic therapy using systemic corticosteroids or immunosuppressants, targeted therapy selectively acts on cytokines, receptors or other molecules, reducing side effect risks and increasing treatment effectiveness. The first approved targeted drug for moderate-to-severe AD was dupilumab, which inhibits IL‑4 and IL‑13, key mediators of type 2 inflammation [90–92]. In some countries, various biologics targeting type 2 cytokines are already registered or undergoing clinical trials for efficacy and safety in AD treatment: anti-­IL‑13 (lebrikizumab and tralokinumab), anti-­IL‑5 (mepolizumab and reslizumab); drugs blocking type 2 cytokine receptors (benralizumab (IL‑5Rα), nemolizumab (IL‑31RAα); anti-­IgE (omalizumab and ligelizumab). The efficacy and safety of other drugs targeting other type 2 inflammation mediators such as alarmins IL‑33 (astegolimab, etokimab, itepekimab, MEDI‑3506), IL‑33 receptor (melrilimab) and TSLP (tezepelumab) are also being studied. Table 2 presents the main targeted biologics acting on key type 2 inflammation cytokines, their biological targets and indications.

Table 2
Targeted biologic therapies for type 2 inflammation

 Targeted biologic drug / References

 Biological targets and effects

 Therapeutic indications

 Dupilumab / [91–96]

 IL‑4 (IL‑4Rα, IL‑13Rα)

 AD, asthma, CRSwNP, EoE, prurigo nodularis, COPD (approved)Bullous pemphigoid, CSU, CIU, allergic fungal rhinosinusitis, ABPA (phase 3) Food allergy, pollen allergy (phase 2)

 Tralokinumab / [97, 98]

 IL‑13(IL‑13Rα2)

 AD (approved in EU)

 Cendakimab /[99, 100]

 IL‑13 (IL‑13Rα2)

 AD (phase 2)EoE (phase 3)

 Lebrikizumab /[101–103]

 IL‑13 (IL‑13Rα1)

 AD (phase 3)

 Nemolizumab /[104–106]

 IL‑31 (IL‑31Rα)

 AD (phase 3)Prurigo nodularis (phase 3)Chronic itch (phase 2)

 Mepolizumab /[14, 35, 107–110]

 IL‑5

 Asthma, EGPA, HES (approved)COPD, nasal polyposis (phase 3)EoE (phase 3)

 Reslizumab /[14, 111–113]

 IL‑5

 Asthma (approved)Sinusitis (phase 3)EGPA

 Depemokimab / [114]

 IL‑5

 Asthma (phase 3)

 Benralizumab /[112, 115–119]

 IL‑5 (IL‑5Rα)

 Asthma (approved)Bullous pemphigoid, COPD, EoE, EGPA, HES, Nasal polyposis (phase 3)AD, CSU, Rhinosinusitis, Eosinophilic gastroenteritis (phase 2)

 Tezepelumab /[120–122]

 TSLP

 Asthma (approved), CRSwNP (phase 3)CSU, COPD (phase 2)

 Astegolimab / [123, 124]

 IL‑33 (IL‑33R)

 Asthma, COPD (phase 2)

 Itepekimab /[125]

 IL‑33

 COPD (phase 3)

 Tozorakimab /[126]

 IL‑33

 Asthma, AD, COPD, COVID‑19 (phase 2)

 Omalizumab /[127–132]

 IgE

 Asthma, CSU, nasal polyposis, seasonal AR (approved)Food allergy (phase 3)

 Ligelizumab /[133, 134]

 IgE

 CSU, Food allergy (phase 3)

 Fezakinumab /[135]

 IL‑22

 AD (phase 2)

Note: CRSwNP — Chronic rhinosinusitis with nasal polyps; EoE — Eosinophilic esophagitis; COPD — Chronic obstructive pulmonary disease; ABPA — Allergic bronchopulmonary aspergillosis; CSU — Chronic spontaneous urticaria; CIU — Chronic inducible urticaria; EGPA — Eosinophilic granulomatosis with polyangiitis; HES — Hypereosinophilic syndrome; AR — Allergic rhinitis.

Interestingly, the clinical efficacy of targeted drugs against type 2 cytokines has provided deeper insights into their role not only in AD but also in other diseases such as asthma, chronic rhinosinusitis with nasal polyps, and eosinophilic esophagitis. The lack of efficacy of some targeted drugs in clinical trials has proven highly valuable for understanding the precise mechanisms underlying type 2 inflammatory diseases and their treatment. For instance, the limited effectiveness of mepolizumab [107], omalizumab [130], and ligelizumab [136] in AD suggested that IL‑5‑mediated peripheral blood eosinophilia is not the primary source of the inflammatory cascade in AD, and that extremely high IgE levels do not play a dominant role in disease symptom development. On the other hand, the use of certain biologic targeted drugs, such as anti-­TNF [137], anti-­IL‑17 [138], and anti-­IL‑12/23 [139], demonstrated moderate clinical efficacy but was associated with an increased risk of opportunistic and/or serious bacterial, fungal, or viral infections.

JAK inhibitors

The JAK-STAT signaling system (Janus Kinases — signal transducer and activator of transcription) is a pathway consisting of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) proteins, which transmits information from extracellular polypeptide signals through transmembrane receptors directly to target gene promoters in the nucleus. In AD, this signaling system plays a critical role in activating type 2 immune responses via IL‑4, eosinophil activation, and B-cell differentiation. JAK inhibitors were initially approved for rheumatoid arthritis, psoriasis, and alopecia. The JAK1/JAK3 inhibitor tofacitinib is approved for rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis; pilot studies have also explored its efficacy in AD. Results from oral tofacitinib use in a small group (six AD patients) for 8–29 weeks showed a 66.6% reduction in SCORAD index, with no adverse events reported [140]. A study of topical 2% tofacitinib ointment in 69 adult AD patients confirmed its clinical efficacy compared to placebo [141]. Another JAK inhibitor, delgocitinib, has broad-­spectrum activity, suppressing Th1, Th2, and Th17 responses by inhibiting JAK1, JAK2, JAK3, and TYK2. Its topical form is approved in Japan for AD treatment [142], with efficacy demonstrated over 28 and 52 weeks [143, 144]. A study in 22 children aged 6–24 months applied 0.25% or 0.5% delgocitinib ointment twice daily for 52 weeks, showing a –73.5% reduction in modified Eczema Area and Severity Index (mEASI) by week 4, –81.7% by week 28, and –81.9% by week 52, with no treatment-­related adverse events [145].

The JAK1/JAK2 inhibitor ruxolitinib carries high immunosuppression and infection risks when administered orally. Its topical form is approved in the U.S. for short-term, intermittent treatment of mild-to-moderate AD in patients ≥12 years without immunosuppression, when other topical therapies are inadequate or contraindicated. Two Phase III trials (TRuE-AD1 and TRuE-AD2) demonstrated the efficacy and safety of 0.75% and 1.5% ruxolitinib cream in adolescents/adults with mild-to-moderate AD [146].

Baricitinib, a selective JAK1/JAK2 inhibitor, is approved in the EU and Russia for moderate-to-severe AD in adults. Short- and long-term studies showed improved skin condition, reduced itch, better sleep, and enhanced quality of life with 4 mg/day over 16 weeks [147], sustained efficacy at 68 weeks [148].

Next-generation JAK1‑selective inhibitors upadacitinib and abrocitinib are approved in Russia, the EU, U.S., and Japan for AD. Upadacitinib is also approved for six other indications in Russia (rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, non-radiographic axial spondyloarthritis, ulcerative colitis, Crohn’s disease). Its AD profile was evaluated in five trials involving >4,000 patients [149–152]. Abrocitinib is approved for moderate-to-severe AD in adults/adolescents, showing rapid symptom reduction by week 12 versus placebo [153, 154].

A recent network meta-analysis compared abrocitinib, baricitinib, and upadacitinib in moderate-to-severe AD [155]. Analysis of 10 trials revealed all three significantly improved Investigator’s Global Assessment (IGA) and EASI scores. Upadacitinib 30 mg outperformed other doses/drugs in efficacy but had higher adverse event rates; upadacitinib 15 mg and abrocitinib 200 mg showed comparable high efficacy. However, upadacitinib 30 mg may be optimal for short-term use due to its superior efficacy despite higher side effects. JAK inhibitors rapidly reduce itch and AD symptoms by targeting cytokine pathways, but their selectivity in vivo is dose-dependent. Rare adverse effects (cytopenia, gastrointestinal perforation, malignancies) occur more frequently than with biologics, underscoring the need for further optimization in type 2 inflammatory diseases.

Conclusion

Type 2 inflammation plays a pivotal role in the pathogenesis of AD, driving chronic inflammation, skin barrier dysfunction, and the clinical manifestations of the disease. Key mediators of T2 inflammation-­including IL‑4, IL‑5, IL‑13, and IL‑31‑regulate the activation of various immune-­competent cells, not only amplifying inflammation but also contributing to the development of pruritus. This, in turn, establishes the self-perpetuating “itch-scratch” cycle, which exacerbates skin damage and further stimulates inflammatory processes. Impaired skin barrier function also facilitates the penetration of allergens and microbial agents, further activating the immune response and worsening disease severity. The advent of targeted biologic therapies, such as dupilumab, lebrikizumab, and tralokinumab, has opened new avenues for AD treatment by specifically blocking key type 2 cytokines. These targeted approaches have already demonstrated efficacy in reducing inflammation, alleviating pruritus, and restoring skin barrier function. However, not all biologics have proven equally effective, highlighting the need for further research into disease mechanisms. For example, the lack of significant clinical benefit from IL‑5 inhibition underscores the complexity of the inflammatory cascade and points to the importance of other mechanisms, including microbiome disturbances and autoimmune processes. Future research should focus on deepening our understanding of the interactions between the immune system, epidermal barrier, and environmental, genetic, and epigenetic factors that may influence disease severity and treatment response. Additionally, it is important to consider ethnic and geographic differences in the clinical presentation and pathogenesis of AD to enable the development of personalized treatment approaches.

In summary, studying type 2 inflammation as a central mechanism in AD pathogenesis not only advances our understanding of the disease but also facilitates the development of new therapeutic strategies to control AD and improve patients’ quality of life, which remains a priority in contemporary immunology, allergology, and dermatology.

×

About the authors

Olga G. Elisyutina

National Research Center - Institute of Immunology FMBA of Russia; RUDN University

Author for correspondence.
Email: el-olga@yandex.ru
ORCID iD: 0000-0002-4609-2591
SPIN-code: 9567-1894
Moscow, Russian Federation

Evgenii V. Smolnikov

National Research Center - Institute of Immunology FMBA of Russia; RUDN University

Email: el-olga@yandex.ru
ORCID iD: 0000-0003-1302-4178
SPIN-code: 4874-8100
Moscow, Russian Federation

Daria D. Chernushevich

National Research Center - Institute of Immunology FMBA of Russia; RUDN University

Email: el-olga@yandex.ru
ORCID iD: 0000-0003-0006-2773
SPIN-code: 2497-5608
Moscow, Russian Federation

Alla O. Litovkina

National Research Center - Institute of Immunology FMBA of Russia; RUDN University

Email: el-olga@yandex.ru
ORCID iD: 0000-0002-5021-9276
SPIN-code: 2337-7930
Moscow, Russian Federation

Maria G. Byazrova

National Research Center - Institute of Immunology FMBA of Russia; RUDN University

Email: el-olga@yandex.ru
ORCID iD: 0000-0002-9858-7596
SPIN-code: 4317-9042
Moscow, Russian Federation

Elena A. Levkova

RUDN University

Email: el-olga@yandex.ru
SPIN-code: 6407-9880
Moscow, Russian Federation

Elena S. Fedenko

National Research Center - Institute of Immunology FMBA of Russia

Email: el-olga@yandex.ru
ORCID iD: 0000-0003-3358-5087
SPIN-code: 5012-7242
Moscow, Russian Federation

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