Pathogenesis of Atopic Dermatitis and the Role of the Janus Kinase-signal Transducer and Activator of Transcription Pathway
Atopic dermatitis is a multifactorial and extremely heterogeneous disease that includes both genetic and environmental factors. It is strongly associated with other atopic comorbidities such as asthma, allergic rhinitis, and food allergies; however, the mechanism linking these disorders is not completely understood.[14–16]
Atopic dermatitis is characterized by skin epidermal barrier disruption, epidermal hyperplasia, and chronic inflammation with increased cellular infiltrates, including T cells, dendritic cells, and eosinophils.[17–19] The epidermal barrier dysfunction includes not only filaggrin mutations, but also diminished expression of epidermal structural proteins or lipids, in part in response to upregulation of type-2 immunity cytokines, such as IL-4, IL-13, and IL-33.[4,20,21] Mutations in the epidermal structure protein filaggrin pose a genetic risk for developing AD; however, most patients with AD do not have these mutations.[22,23]
Similarly to psoriasis, AD is also associated with T cell activation in the skin and blood, although in a more heterogeneous fashion. Atopic dermatitis skin shows robust T helper (Th)2/Th22-centered inflammation throughout its course, with some Th1 and Th17 components.[4,17,25] Acute AD skin lesions are characterized by increases in Th2/Th22-related cytokines and chemokines and some Th17-related signals. With disease progression, intensification of these axes, as well as Th1 pathway polarization, contribute to the chronic phenotype.[17,27,28] The contribution of each pathway to the clinical presentation of AD across its various phenotypes remains not completely defined, as AD involves distinct clinical subtypes and molecular phenotypes.[24–29] High levels of inflammatory cytokines are present in lesional skin, including Th2 (IL-4, IL-13, IL-31), Th22 (IL-22), and Th1 cytokines (interferon [IFN]-γ).[30–32] Despite the fact that the function of Th1 and Th17 cell-mediated responses is still unknown, they seem to be overexpressed in chronic disease stages, especially in Asian-origin AD and pediatric AD.[17,21,33]
The Th2 cytokines IL-4 and IL-13 were shown to modulate the skin barrier integrity by inhibiting the expression of key differentiation proteins, such as filaggrin, involucrin, and loricrin, and of tight junctions, conducting to the increased penetration of allergens and pathogens.[34,35] Additionally, downstream signaling of IL-4 and IL-13 prevents the induction of innate immune response genes, such as β-defensins and cathelicidin, therefore increasing the susceptibility of patients with AD to cutaneous infections caused by Staphylococcus aureus and herpes simplex virus.[36–39]
As AD has multi-cytokine polarization, a treatment strategy that is able to inhibit more than one cytokine pathway is conceptually appealing to achieve greater efficacy. Several cytokines involved in the pathogenesis of AD act via intracellular signaling that encompasses the JAK-STAT pathway. The JAK-STAT pathway is a master regulator of immune function, implicated in the downstream signaling of inflammatory cytokines, including ILs, IFNs, and multiple growth factors.[41–43] In fact, thymic stromal lymphopoietin, IL-4, IL-5, IL-13, IL-22, IL-24, and IL-31 require JAK-STAT downstream signaling for their biological function. Some mutations and polymorphisms occurring within the JAK-STAT pathway have been implied in both autoimmune and malignant processes. Additionally, dysregulation of JAK-STAT signaling has been reported as a possible mechanism in many dermatoses, including AD.[43–48] Furthermore, preclinical research evidence has showed that chronic itch depends upon neuronal JAK1 signaling, thus blocking JAK1 in these patients might improve pruritus, thereby supporting a potential role for JAK inhibitors in the treatment of AD.
The mammalian JAK kinase family is composed of three JAKs (JAK1, JAK2, JAK3) and tyrosine kinase 2 (TYK2), which selectively bind distinct receptor chains, acting intracellularly as signal transducers, triggered by several cytokines. Janus kinases activate STAT proteins that function as transcription factors, translocating to the nucleus and upregulating genes responsible for the production of proinflammatory cell surface cytokines and growth factors. Janus kinase family members act in pairs in the intracytoplasmatic portion of the cytokine receptor. Each pair can be activated by different cytokines and, in turn, switch on distinct STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6). These various combinations determine different features of immune-cell development and function. Janus kinase 1 dimerizes with JAK2, JAK3, or TYK2,; JAK2 dimerizes with itself, JAK1, or TYK2 and is mainly implicated in hematopoietic Signalling; JAK3 only dimerizes with JAK1 and is preferentially expressed in lymphocytes and mast cells; and TYK2 dimerizes with JAK1 or JAK2 and transduces a signal from IL-10, IL-12, and IL-23 and IFN receptors.[54,55] Contrary to other immune-mediated diseases, there is an enhanced signaling through all four JAKs in AD.[56,57] Interleukin-4 and IL-13 bind to IL-4 receptor-α and either the γ-chain or IL-13 receptor-α1 to activate JAK1/3, thus leading to the activation of STAT6.[56,57] This activation leads to augmented expression of periostin, a proinflammatory extracellular matrix protein that is trophic to keratinocytes, promoting them to produce thymic stromal lymphopoietin, which activate JAK1/2 signaling. Interleukin-22, which binds its cognate receptor, leading to activation of JAK1 and TYK2 and phosphorylation of STAT3,[59–61] is also elevated in AD lesions and is associated with epidermal thickening, skin barrier disruption, and increased expression of thymic stromal lymphopoietin and IL-33 cytokines (non-associated with JAK signaling).[31,32] Additionally, IL-31 (JAK1/2) acts on keratinocytes enhancing IL-24 (JAK1/TYK2) release, leading to diminished production of filaggrin and consequent skin barrier dysfunction.[1,4] The JAK-STAT pathway regulates multiple steps in the AD pathogenesis, which makes the new class of small-molecule agents named JAK inhibitors attractive for the treatment of AD (Table 1).
Am J Clin Dermatol. 2020;21(6):783-798. © 2020 Adis Springer International Publishing AG