Targeting the Janus Kinase Family in Autoimmune Skin Diseases

Abstract

Autoimmune skin diseases are characterized by significant local and systemic inflammation that is largely mediated by the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. Advanced understanding of this pathway has led to the development of targeted inhibitors of Janus kinases (JAKinibs). As a class, JAK inhibitors effectively treat a multitude of hematologic and inflammatory diseases. Growing evidence suggests that JAK inhibitors are efficacious in atopic dermatitis, alopecia areata, psoriasis, and vitiligo. Additional evidence suggests that JAK inhibition might be broadly useful in dermatology, with early reports of efficacy in several other conditions. JAK inhibitors can be administered orally or used topically and represent a promising new class of medications. Here we review the evolving data on the role of the JAK-STAT pathway in inflammatory dermatoses and the potential therapeutic benefit of JAK-STAT antagonism.

Keywords: Janus kinase; autoimmunity; cytokines; dermatology; skin barrier.

Figure 1

JAK-STAT signaling pathways. Janus kinases (JAK1-3, TYK2) are activated by more than 60 extracellular stimuli and phosphorylate downstream STAT proteins, which translocate to the nucleus and activate target genes. EPO, erythropoietin; GH, growth hormone; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; JAK, Janus kinases; JAKinibs, Janus kinase inhibitors; STAT, signal transducer and activator of transcription; TPO, thrombopoietin; TSLP, thymic stromal lymphopoietin; TYK2, tyrosine kinase.

Figure 2

JAK-mediated cytokine signaling in T helper subsets. Ligand binding to its cognate receptor triggers JAK-STAT activation and plays a central role in naive T-cell differentiation into Th1, Th2, and Th17 subsets. ACT, Nuclear factor NF-kappa-B activator 1; GATA, GATA transcription factor 3; IFN, interferon; IL, interleukin; JAK, Janus kinase; PI3K, Phosphoinositide 3-kinases; RORγt, retinoic acid receptor-related orphan receptor γ; STAT, signal transducer and activator of transcription; T-bet, T-box transcription factor TBX21; Th, T helper; TGF, transforming growth factor; TNF, tumor necrosis factor; TYK, tyrosine kinase.

Figure 3

Immunopathogenesis of atopic dermatitis. Allergen entry through the disrupted epidermal barrier stimulates keratinocytes to express cytokines, such as IL-33 and TSLP, which trigger ILC2 and Th2 cell mediated inflammation. Skin-resident dendritic cells take up exogenous and self-antigens released from damaged cells and promote type 2 immunity. CD8+ T cells infiltrate atopic dermatitis skin and activate Th2 cells to further release IL-4 and IL-13, which promotes IgE class switching. Cytokines released from skin infiltrating Th17 and Th22 lymphocytes synergize, leading to further barrier impairment and epidermal hyperplasia. DC, dendritic cell; FLG, Filaggrin; Ig, immunoglobulin; IL, interleukin; ILC2, type 2 innate lymphoid cells; INV, Involucrin; LC, Langerhans cell; LOR, Loricrin; OSM, Oncostatin M; OSMRβ, Oncostatin M receptor β; Th, T helper; TSLP, thymic stromal lymphopoietin.

Figure 4

IFNγ-driven inflammation in alopecia areata is JAK mediated. CD8⁺ T cells infiltrate the dermis, localize to the hair follicle bulb, and release IFNγ. IFNγ binds the IFN receptor on the surface of the follicular epithelial cell, which in turn signals via JAK1 and JAK2 to promote production of IL-15, a mediator of CD8⁺ T-cell activation. IL-15 binds IL-15 receptor on the CD8⁺ T cell surface, resulting in signaling via JAK1 and JAK3 to enhance the production of IFNγ and amplify the feedback loop. CD8⁺ T cells then attack the hair follicle, which causes hair loss. CXCL, chemokine (C-X-C motif) ligand; IFN, interferon; JAK, Janus kinase.

Figure 5

IFNγ-driven inflammation in vitiligo is JAK mediated. Intrinsic and/or extrinsic factors induce the cellular stress response in melanocytes, which then activates innate immunity within the skin to trigger the initial inflammation that leads to autoimmunity. As a result, CXCL9 and CXCL10 are released from keratinocytes leading to recruitment of CD8⁺ T cells. Activated CD8⁺T cells produce IFNγ which trigger more CXCL9 and CXCL10 production from keratinocyte through JAK1 and JAK2 signaling and recruit more CD8⁺ T cells to the inflamed sites. CD8⁺ T cells then destruct melanocytes and lead to depigmentation. CXCL, chemokine (C-X-C motif) ligand; IFN, interferon; IL, interleukin; JAK, Janus kinase; NKD2D, natural killer group 2D.