Understanding Type 2 and Non-Type 2 Inflammation in Atopic Dermatitis

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder. It involves cycles of flare-ups and remissions triggered by a variety of stressors, including allergens and irritants, infections, weather changes, and stress.^1–3

While acute AD flares are mainly Th2 driven, chronic AD includes non-type 2 inflammatory responses, involving Th1, Th17 and Th22 cells.¹ AD is, therefore, a clinically and molecularly heterogeneous disease, with several inflammatory endotypes defined by specific molecular mechanisms.¹

There is an unmet need for therapies that target alternative immune pathways involved in disease initiation and maintenance, beyond the cytokines driving inflammation, including non-type 2 inflammatory profiles.^4,5

The Role of Type 2 Inflammation in Atopic Dermatitis

Atopic dermatitis is characterised by dry skin, erythematous rash and intense pruritus.³

The etiology of AD is a complex combination of genetics, immune dysregulation and environmental factors, all contributing to the development of the disease.^1–3 In particular, skin barrier impairment, an abnormal immune response and the interplay between these two factors, are key features of AD pathogenesis.⁶

In approximately 80% of patients with AD, the immune response features an enhanced type 2 response, dominated by Th2 cells, IgE production as well as eosinophil and mast cell recruitment.^1,7

Understand more about disease burden for moderate-to-severe AD patients.

How does Type 2 Inflammation Affect the Pathogenesis of Atopic Dermatitis?

Persistent Th2 activation is associated with epidermal barrier dysfunction, immune dysregulation and pruritogenic neural signaling.⁷ Importantly, immune dysregulation contributes to both the initiation and the perpetuation of AD, with the contribution of both the innate and adaptive immune responses to type 2 inflammation.^3,7,8

Itch and itch sensitization in AD are caused by the activation of sensory neurons by alarmins (released by damaged epithelial cells) and type 2 cytokines (produced by immune cells).⁸ Itch, in turn, triggers chronic scratching that exposes antigen-presenting cells to allergens and microbes, sustaining Th2-driven inflammation.⁷

Immune abnormalities affect both lesional and non-lesional AD skin, and entail an increase in infiltrating T cells, dendritic cells and Langerhans cells, in comparison to healthy skin.⁹

AD is more recently regarded as a systemic disorder: as a matter of fact, systemic inflammation is also present in the majority of patients with AD, showing increased circulating Th2, eosinophils and IgE.^3,9

Key Type 2 Cytokines in Atopic Dermatitis

IL-4, IL-13 and IL-31 are the key Th2 cytokines driving AD pathogenesis in most patients.¹

An important feature of the Th2 pathway in AD is the overproduction of IL-31, a pruritogenic cytokine that contributes to the itch-scratch cycle, while IL-13 is upregulated upon scratching and in response to mechanical skin injury. ^4,7

IL-4 and IL-13 promote IgE production, eosinophil recruitment and contribute to skin barrier disruption.⁷

Learn more about the immune pathways driving T cell inflammation.

Skin Barrier Disruption and Cutaneous Inflammation in Atopic Dermatitis

The core mechanism of AD is a vicious cycle, where skin barrier disruption causes type 2 inflammation, and type 2 inflammation worsens barrier dysfunction.^5,6 Skin barrier disruption in AD is characterized by keratin dysregulation, increased serine protease activity, altered lipid composition and disrupted tight junctions.⁶

Reduced expression and loss-of-function mutations in the filaggrin gene (FLG), a necessary structural protein for epidermal barrier integrity, are the main genetic risk factors associated to AD; however, mutations in the FLG gene are not sufficient to cause AD alone.³ Conversely, type 2 inflammatory mediators can reduce filaggrin expression in patients who do not carry any mutation.⁶

Antigens, irritants and microbes can easily cross a disrupted skin barrier, increasing the production of proinflammatory cytokines and perpetuating the cycle.³

Subclinical Inflammation in Atopic Dermatitis

Subclinical inflammation in AD is defined as a persistent inflammatory status, invisible to the naked eye, that precedes and follows visible inflammation, lasting after acute symptoms are resolved.¹⁰ It is characterized by barrier dysfunction, persistent proinflammatory environment and increased bacterial colonization in both normal-appearing, non-lesional skin and post-treatment lesional skin.¹⁰

Current treatment approaches are directed at treating uncontrolled active lesions or at preventing future flares in the same areas.³ According to the AAD guidelines, topical anti-inflammatory therapies have so far been the pillar of induction and maintenance therapy for mild to moderate AD, but systemic therapies may be required for patients with severe or poorly controlled disease.^3,11,12

Learn more about the unmet need and patient burden in AD.

Exploring Non-Type 2 Inflammation in Atopic Dermatitis

Although traditionally associated with type 2 inflammation, different endotypes of AD exhibit different cytokine profiles and are driven by different Th cell subsets.¹

Th1, Th17 and Th22 cells are involved in AD pathogenesis.¹ In particular, AD chronic inflammation is usually characterised by the initiation of Th1 responses, and by sustained Th2 and Th22 activation.¹³

Th1 and Th17 Responses in Atopic Dermatitis

The transition from acute to chronic inflammation in AD is usually marked by the start of Th1 response, which is upregulated in chronic lesions.^2,13

Th17 response contributes to neutrophilic inflammation, and is especially upregulated in acute AD skin lesions in Asian patients.^1,2,13 Notably, IL-17 reduces the expression of filaggrin and involucrin, essential for skin barrier integrity.¹³

Th22 Response in Atopic Dermatitis

Th22 cell are involved in the chronic phase of AD, by driving epidermal hyperplasia and perpetuating skin barrier disruption.¹ Moreover, IL-22 upregulation is associated with abnormal epidermal markers, such as keratin 6 and keratin 16.¹³

The endotype driven by the Th22 response, prominent in patients with chronic AD lesions, is known as the IL-22 high endotype, and is associated with epidermal thickening and altered skin microbiota.¹

Therapeutic Strategies for Type 2 and Non-Type 2 Inflammation in Atopic Dermatitis

The treatment landscape of AD has evolved with the identification of different immunological targets, with treatment goals shifting from alleviating symptoms to treating the underlying causes of the disease.^4,7 This is particularly relevant for chronic AD, where disease-modifying drugs are needed to prevent disease progression and reduce long-term consequences.⁴

AD involves multiple inflammatory pathways and diverse T-cell subsets. ¹ While many current treatments have made great strides in improving patient outcomes in AD, there still exists an unmet need.⁴

Many existing therapies selectively target individual inflammatory pathways or cytokines, not accounting for the molecular heterogeneity of the disease.^1,8 Though it is now known that AD involves multiple T-cell subsets and immune pathways, many available therapies are predominantly directed toward type 2 inflammatory mediators, which are mostly effective in patients with a Th2-dominant AD endotype.^4,7

As such, there is an unmet need for therapies that target alternative immune pathways involved in disease initiation and maintenance, not only the cytokines driving inflammation, as well as those for non-type 2 inflammatory profiles.^4,5

Explore current paradigms and unmet needs in systemic and long-term atopic dermatitis treatment.

Abbreviations

AD, atopic dermatitis; FLG, filaggrin; IgE, immunoglobulin E; IL, interleukin; Th, T helper lymphocytes;

References

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2. Guttman-Yassky E, Renert-Yuval Y, Brunner PM. Atopic dermatitis. Lancet. 2025;405(10478):583-596. doi:10.1016/S0140-6736(24)02519-4
3. Jeskey J, Kurien C, Blunk H, et al. Atopic dermatitis: A review of diagnosis and treatment. J Pediatr Pharmacol Ther. 2024;29(6):587-603. doi:10.5863/1551-6776-29.6.587
4. Prados-Carmona A, Husein-ElAhmed H, Navarro-Triviño FJ, Ruiz-Villaverde R. From pathways to patients in atopic dermatitis: Advanced systemic therapies. Int J Mol Sci. 2025;26(23):11487. doi:10.3390/ijms262311487
5. Qin J, Meng Z, Min W, Wang X, Zou Y. Immunological antagonism between psoriasis and atopic dermatitis: Pathways, clinical implications, and therapeutic perspectives. Clin Cosmet Investig Dermatol. 2025;18:3605-3619. doi:10.2147/CCID.S574980
6. Beck LA, Cork MJ, Amagai M, et al. Type 2 inflammation contributes to skin barrier dysfunction in atopic dermatitis. JID Innov. 2022;2(5):100131. doi:10.1016/j.xjidi.2022.100131
7. Pala V, Rosset F, Mastorino L, et al. The central role of Th2 immune response in inflammatory dermatoses: From pathogenesis to targeted therapies. Int J Mol Sci. 2025;26(21):10720. doi:10.3390/ijms262110720
8. Moniaga CS, Tominaga M, Takamori K. The pathology of type 2 inflammation-associated itch in atopic dermatitis. Diagnostics (Basel). 2021;11(11):2090. doi:10.3390/diagnostics11112090
9. Gittler JK, Krueger JG, Guttman-Yassky E. Atopic dermatitis results in intrinsic barrier and immune abnormalities: implications for contact dermatitis. J Allergy Clin Immunol. 2013;131(2):300-313. doi:10.1016/j.jaci.2012.06.048
10. Tang TS, Bieber T, Williams HC. Are the concepts of induction of remission and treatment of subclinical inflammation in atopic dermatitis clinically useful? J Allergy Clin Immunol. 2014;133(6):1615-1625.e1. doi:10.1016/j.jaci.2013.12.1079
11. Sidbury R, Alikhan A, Bercovitch L, et al. Guidelines of care for the management of atopic dermatitis in adults with topical therapies. J Am Acad Dermatol. 2023;89(1):e1-e20. doi:10.1016/j.jaad.2022.12.029
12. Davis DMR, Drucker AM, Alikhan A, et al. Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies. J Am Acad Dermatol. 2024;90(2):e43-e56. doi:10.1016/j.jaad.2023.08.102
13. Kim J, Kim BE, Leung DYM. Pathophysiology of atopic dermatitis: Clinical implications. Allergy Asthma Proc. 2019;40(2):84-92. doi:10.2500/aap.2019.40.4202