Delineating the Healthy Human Skin UV Response and Early Induction of Interferon Pathway in Cutaneous Lupus Erythematosus

Katayama, Shintaro; Panelius, Jaana; Koskenmies, Sari; Skoog, Tiina; Mähönen, Katariina; Kisand, Kai; Bondet, Vincent; Duffy, Darragh; Krjutškov, Kaarel; Kere, Juha; Ranki, Annamari

doi:10.1016/j.jid.2019.02.035

Cited by 16 publications

(11 citation statements)

References 24 publications

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“…When nuclear components, such as endogenous nucleic acid motifs, are released out of the nucleus due to cellular damage, they can be perceived as danger associated molecular patterns (DAMPs) (9). There is evidence that keratinocytes and particularly plasmacytoid dendritic cells (pDCs) react on DAMPs inappropriately with immense type I IFN production through Toll-like receptor (TLR)-dependent or -independent pathways in CLE (10)(11)(12). Undergoing an autocrine loop IFNs bind to IFN-α/β receptors on keratinocytes, thus activating JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway and expression of proinflammatory mediators such as CXCL10.…”

Section: Introductionmentioning

confidence: 99%

Selective Janus Kinase 1 Inhibition Is a Promising Therapeutic Approach for Lupus Erythematosus Skin Lesions

et al. 2020

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Background: Cutaneous lupus erythematosus (CLE) is an interferon (IFN)-driven autoimmune skin disease characterized by an extensive cytotoxic lesional inflammation with activation of different innate immune pathways. Aim of our study was to investigate the specific role of Janus kinase 1 (JAK1) activation in this disease and the potential benefit of selective JAK1 inhibitors as targeted therapy in a preclinical CLE model. Methods: Lesional skin of patients with different CLE subtypes and healthy controls (N = 31) were investigated on JAK1 activation and expression of IFN-associated mediators via immunohistochemistry and gene expression analyses. The functional role of JAK1 and efficacy of inhibition was evaluated in vitro using cultured keratinocytes stimulated with endogenous nucleic acids. Results were confirmed in vivo using an established lupus-prone mouse model. Results: Proinflammatory immune pathways, including JAK/STAT signaling, are significantly upregulated within inflamed CLE skin. Here, lesional keratinocytes and dermal immune cells strongly express activated phospho-JAK1. Selective pharmacological JAK1 inhibition significantly reduces the expression of typical proinflammatory mediators such as CXCL chemokines, BLyS, TRAIL, and AIM2 in CLE in vitro models and also improves skin lesions in lupus-prone TREX1 −/−-mice markedly. Conclusion: IFN-associated JAK/STAT activation plays a crucial role in the pathophysiology of CLE. Selective inhibition of JAK1 leads to a decrease of cytokine expression, reduced immune activation, and decline of keratinocyte cell death. Topical treatment with a JAK1-specific inhibitor significantly improves CLE-like skin lesions in a lupus-prone TREX1 −/−-mouse model and appears to be a promising therapeutic approach for CLE patients.

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Section: Introductionmentioning

confidence: 99%

Selective Janus Kinase 1 Inhibition Is a Promising Therapeutic Approach for Lupus Erythematosus Skin Lesions

et al. 2020

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“…Skin gene expression of complement has been shown to be more dysregulated relative to blood gene expression in CLE ( 74 , 79 , 80 ). This is contrasted with the upregulation of cathepsins associated with lysosomes and proteasome-related genes in CLE peripheral blood relative to lesional skin ( 35 , 74 ). The complex dysregulation of the systems involved in the clearance of cellular debris at a localized and systemic level highlights the complexity of the pathogenesis of CLE.…”

Section: Resultsmentioning

confidence: 78%

“…UVB irradiation induces chemokines, such as CXCR3 ligands CXCL9, CXCL10, and CXCL11, necessary to orchestrate the innate and adaptive response central to the immunopathogenesis of CLE ( 34 ). More recently, Katayama et al ( 35 ) showed upregulation of the IFIT gene family, HLA-DPA1 , and normal UV response genes (i.e., nucleic acid binding and erythematous reactions) in CLE skin relative to healthy skin. The IFIT gene family has subsequently been shown to be the top hub genes in bioinformatics analysis of DLE skin ( 36 ).…”

Section: Resultsmentioning

confidence: 99%

The Genetic Landscape of Cutaneous Lupus Erythematosus

2022

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Cutaneous lupus erythematosus (CLE) is an autoimmune connective tissue disease that can exist as a disease entity or within the context of systemic lupus erythematosus (SLE). Over the years, efforts to elucidate the genetic underpinnings of CLE and SLE have yielded a wealth of information. This review examines prior studies investigating the genetics of CLE at the DNA and RNA level and identifies future research areas. In this literature review, we examined the English language literature captured within the MEDLINE and Embase databases using pre-defined search terms. First, we surveyed studies investigating various DNA studies of CLE. We identified three predominant areas of focus in HLA profiling, complement deficiencies, and genetic polymorphisms. An increased frequency of HLA-B8 has been strongly linked to CLE. In addition, multiple genes responsible for mediating innate immune response, cell growth, apoptosis, and interferon response confer a higher risk of developing CLE, specifically TREX1 and SAMHD1. There was a strong association between C2 complement deficiency and CLE. Second, we reviewed literature studying aberrations in the transcriptomes of patients with CLE. We reviewed genetic aberrations initiated by environmental insults, and we examined the interplay of dysregulated inflammatory, apoptotic, and fibrotic pathways in the context of the pathomechanism of CLE. These current learnings will serve as the foundation for further advances in integrating personalized medicine into the care of patients with CLE.

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“…Thereafter, TNF-α is secreted in a Toll/IL-1R domain-containing adaptor-inducing IFN- β (TRIF)-dependent manner ( 30 ). After photoprovocation, certain nucleosome subunits as well as small nuclear ribonucleoproteins were upregulated, which are known as autoantigens in SLE ( 31 ). This shows that expression of autoantigens also occurs in healthy skin after UV light exposure ( 31 ).…”

Section: Effects Of Ultraviolet Irradiation On Healthy Skinmentioning

confidence: 99%

Current concepts of photosensitivity in cutaneous lupus erythematosus

Klein

Kunz

2022

Front. Med.

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Cutaneous lupus erythematosus (CLE) represents a complex autoimmune disease with a broad phenotypic spectrum ranging from acute to chronic destructive cutaneous lesions. Patients with CLE exhibit high photosensitivity and ultraviolet (UV) irradiation can lead to systemic flares in systemic lupus erythematosus. However, the exact mechanisms how UV irradiation enhances cutaneous inflammation in lupus are not fully understood. Recently, new molecular mechanisms of UV-driven immune responses in CLE were identified, offering potential therapeutic approaches. Especially the induction of type I interferons, central cytokines in lupus pathogenesis which are released by various skin cells, have become the focus of current research. In this review, we describe current pathogenic concepts of photosensitivity in lupus erythematosus, including UV-driven activation of intracellular nucleic acid sensors, cellular cytokine production and immune cell activation. Furthermore, we discuss activated pathways contributing to enhanced apoptosis as well as intracellular translocation of autoantigens thereby promoting CLE upon UV light exposure.

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Delineating the Healthy Human Skin UV Response and Early Induction of Interferon Pathway in Cutaneous Lupus Erythematosus

Cited by 16 publications

References 24 publications

Selective Janus Kinase 1 Inhibition Is a Promising Therapeutic Approach for Lupus Erythematosus Skin Lesions

Selective Janus Kinase 1 Inhibition Is a Promising Therapeutic Approach for Lupus Erythematosus Skin Lesions

The Genetic Landscape of Cutaneous Lupus Erythematosus

Current concepts of photosensitivity in cutaneous lupus erythematosus

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