Multiple Roles for Cytokines in Atopic Dermatitis: From Pathogenic Mediators to Endotype-Specific Biomarkers to Therapeutic Targets

Abstract

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, which generally presents with intense itching and recurrent eczematous lesions. AD affects up to 20% of children and 10% of adults in high-income countries. The prevalence and incidence of AD have increased in recent years. The onset of AD mostly occurs in childhood, although in some cases AD may persist in adult life or even manifest in middle age (adult-onset AD). AD pathophysiology is made of a complex net, in which genetic background, skin barrier dysfunction, innate and adaptive immune responses, as well as itch contribute to disease development, progression, and chronicization. One of the most important features of AD is skin dehydration, which is mainly caused by filaggrin mutations that determine trans-epidermal water loss, pH alterations, and antigen penetration. In accordance with the "outside-inside" theory of AD pathogenesis, in a context of an altered epidermal barrier, antigens encounter epidermal antigen presentation cells (APCs), such as epidermal Langerhans cells and inflammatory epidermal dendritic cells, leading to their maturation and Th-2 cell-mediated inflammation. APCs also bear trimeric high-affinity receptors for immunoglobulin E (IgE), which induce IgE-mediated sensitizations as part of pathogenic mechanisms leading to AD. In this review, we discuss the role of cytokines in the pathogenesis of AD, considering patients with various clinical AD phenotypes. Moreover, we describe the cytokine patterns in patients with AD at different phases of the disease evolution, as well as in relation to different phenotypes/endotypes, including age, race, and intrinsic/extrinsic subtypes. We also discuss the outcomes of current biologics for AD, which corroborate the presence of multiple cytokine axes involved in the background of AD. A deep insight into the correlation between cytokine patterns and the related clinical forms of AD is a crucial step towards increasingly personalized, and therefore more efficient therapy.

Keywords: atopic dermatitis; biologics; cytokines; endotypes; intracellular pathways; itch; small-molecule inhibitors.

Figure 1

A simplistic overview of AD pathogenesis. Non-lesional skin has an epidermal barrier deficiency with a reduced diversity of the microbiome. In acute AD lesion, Langerhans cells, IEDC bearing specific IgE bound to the high affinity receptor for IgE, and dermal dendritic cells bind allergens and antigens. Keratinocyte-derived (IL-18, IL-1β, IL-33, TSLP and IL-25) and Th2-cell-derived cytokines IL-4, IL-13, and IL-31 directly activate sensory nerves, which promotes pruritus. During transition to chronicity, itch is amplified by various pruritogens (e.g., antigens and molecular mediators such as histamine and other substances). Scratching exacerbates dermatitis, which may further enhance pruritus and result in an itch/scratch vicious cycle. Chronic AD lesional skin is characterized by the intensification of Th2, Th1, and Th17 responses. DC = dendritic cell, MC = mast cell, IDEC = inflammatory dendritic epidermal cell, ILC = innate lymphoid cell. LC = lymphoid cell, B = B cell, Eo = eosinophile, Ba = basophile, IFN = interferon, IL = interleukin, Th = T-helper cell, Th0 = naive T cell, TNF = tumor necrosis factor, TSLP = thymic stromal lymphopoietin.

Figure 2

A schematic picture of the T cell subsets and cytokine profiles in the main AD endotypes. Adult AD is characterized by the intensification of Th1 signature, whereas pediatric AD shows the predominance of Th17(IL-17A, IL-19, CCL20, LL-37, elafin) and Th9 (IL-9)-related cytokines. Moderate and severe AD share Th2-dependent immune responses, with the identification of Th22 (IL-22), Th1 (IFN-γ, TNF-a, TNF-β), and Th17 (IL-17A and IL-21)-related cytokines in severe AD. Patients with extrinsic AD tend to exhibit barrier disruption, which causes repeated allergen exposure and B-cell activation resulting in hyper-IgE levels in serum. The cytokine spectrum of patients with intrinsic AD is further complicated with additional cytokine axes, including Th1 (IFN-γ, CXCL9, 10, 11) and Th17 (IL-17A, CXCL8).