JAK-STAT signaling pathway in the pathogenesis of atopic dermatitis: An updated review

Abstract

Atopic dermatitis (AD) is a chronic, inflammatory, pruritic form of dermatosis with heterogeneous manifestations that can substantially affect patients' quality of life. AD has a complex pathogenesis, making treatment challenging for dermatologists. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a central role in modulating multiple immune axes involved in the immunopathogenesis of AD. In particular, Th2 cytokines, including interleukin (IL)-4, IL-5, IL-13, IL-31, and thymic stromal lymphopoietin, which contribute to the symptoms of chronic inflammation and pruritus in AD, are mediated by JAK-STAT signal transduction. Furthermore, JAK-STAT is involved in the regulation of the epidermal barrier and the modulation of peripheral nerves related to the transduction of pruritus. Targeting the JAK-STAT pathway may attenuate these signals and show clinical efficacy through the suppression of various immune pathways associated with AD. Topical and oral JAK inhibitors with variable selectivity have emerged as promising therapeutic options for AD. Notably, topical ruxolitinib, oral upadacitinib, and oral abrocitinib were approved by the U.S. Food and Drug Administration for treating patients with AD. Accordingly, the present study reviewed the role of JAK-STAT pathways in the pathogenesis of AD and explored updated applications of JAK inhibitors in treating AD.

Keywords: Janus kinase (JAK); Janus kinase inhibitor; atopic dermatitis (AD); review; signal transducer and activator of transcription (STAT).

Figure 1

Pathogenesis of atopic dermatitis. Background genetic predisposition and environment factors may induce skin barrier impairment along with the invasion of allergens and skin microbiota (mostly Staphylococcus aureus). TSLP, IL-25, and IL-33 released from keratinocytes and activated skin LCs and IDECs lead to the activation of Th2 axis immune response through ILC2 and Th2 cells. In the acute phase of atopic dermatitis, the production of various Th2 cytokines including IL-4, IL-5, IL-13, IL-31 results in barrier dysfunction. In the chronic phase of atopic dermatitis, Th17 and Th22 cytokines cooperatively modulate local inflammation through upregulation of proinflammatory cytokines stimulating epidermal hyperplasia. Th1 immune response also plays a role in the chronic phase of atopic dermatitis. IDEC, inflammatory dendritic epidermal cell; IFN, interferon; IL, interleukin; ILC2, type 2 innate lymphoid cell; LC, Langerhans cell; R, receptor; S. aureus, Staphylococcus aureus; TSLP, thymic stromal lymphopoietin.

Figure 2

JAK-STAT signaling pathway in Th2 axis immune response of atopic dermatitis. IL, interleukin; JAK, Janus kinase; R, receptor; OSMR, oncostatin M receptor; STAT, signal transducer and activator of transcription; TSLP, thymic stromal lymphopoietin.

Figure 3

JAK-STAT signaling pathway in Th17/Th22 axis immune response of atopic dermatitis. C/EBP, CCAAT/enhancer binding protein; IL, interleukin; JAK, Janus kinase; MAPK, mitogen-activated protein kinases; NF, nuclear factor; R, receptor; STAT, signal transducer and activator of transcription; TRAF, tumor necrosis factor receptor-associated factors; TYK2, tyrosine kinase 2.

Figure 4

JAK-STAT signaling pathway in Th1 axis immune response of atopic dermatitis. IFN, interferon; IL, interleukin; JAK, Janus kinase; R, receptor; STAT, signal transducer and activator of transcription.