Type I Immune Response Induces Keratinocyte Necroptosis and Is Associated with Interface Dermatitis

Lauffer, Felix; Jargosch, Manja; Krause, Linda; Garzorz‐Stark, Natalie; Franz, Regina; Roenneberg, Sophie; Böhner, Alexander; Mueller, Nikola S.; Theis, Fabian J.; Schmidt‐Weber, Carsten B.; Biedermann, Tilo; Eyerich, Stefanie; Eyerich, Kilian

doi:10.1016/j.jid.2018.02.034

Cited by 54 publications

(62 citation statements)

References 50 publications

(48 reference statements)

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“…RIPK3 and MLKL activation was demonstrated in podocytes in renal biopsies from patients with lupus nephritis 55 . LP and SLE tissue sections showed enhanced epidermal expression of phosphorylated RIPK3 56 . B cells from SLE patients also significantly displayed high expression levels of necroptosis-related genes 57 .…”

Section: Necroptosis Involved In Human Diseasesmentioning

confidence: 97%

Current translational potential and underlying molecular mechanisms of necroptosis

et al. 2019

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Cell death has a fundamental impact on the evolution of degenerative disorders, autoimmune processes, inflammatory diseases, tumor formation and immune surveillance. Over the past couple of decades extensive studies have uncovered novel cell death pathways, which are independent of apoptosis. Among these is necroptosis, a tightly regulated, inflammatory form of cell death. Necroptosis contribute to the pathogenesis of many diseases and in this review, we will focus exclusively on necroptosis in humans. Necroptosis is considered a backup mechanism of apoptosis, but the in vivo appearance of necroptosis indicates that both caspase-mediated and caspase-independent mechanisms control necroptosis. Necroptosis is regulated on multiple levels, from the transcription, to the stability and posttranslational modifications of the necrosome components, to the availability of molecular interaction partners and the localization of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), receptor-interacting serine/threonineprotein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL). Accordingly, we classified the role of more than seventy molecules in necroptotic signaling based on consistent in vitro or in vivo evidence to understand the molecular background of necroptosis and to find opportunities where regulating the intensity and the modality of cell death could be exploited in clinical interventions. Necroptosis specific inhibitors are under development, but >20 drugs, already used in the treatment of various diseases, have the potential to regulate necroptosis. By listing necroptosis-modulated human diseases and cataloging the currently available drug-repertoire to modify necroptosis intensity, we hope to kick-start approaches with immediate translational potential. We also indicate where necroptosis regulating capacity should be considered in the current applications of these drugs. Facts • Necroptosis is closely associated with the pathogenesis of many human diseases. How effective can the off-label use of already approved drugs in necroptosis-driven diseases be?

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Section: Necroptosis Involved In Human Diseasesmentioning

confidence: 97%

Current translational potential and underlying molecular mechanisms of necroptosis

et al. 2019

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“…It is known that CXCL10 recruits CXCR3 + effector cells and pDCs into skin lesions (2). Those effector cells induce keratinocyte necroptosis, cytokine release and a continuous "self-recruitment" as a hallmark of chronic inflammation (Figure 1) (13).…”

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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“…Recent studies have implicated the role of type I immune responses, specifically type I interferons, in the pathogenesis of interface dermatitis. 9 …”

Section: Discussionmentioning

confidence: 99%

Thymoma-associated multiorgan autoimmunity initially manifested by graft-versus-host disease–like erythroderma: Case report and possible therapeutic role of antimalarial drugs

et al. 2020

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Type I Immune Response Induces Keratinocyte Necroptosis and Is Associated with Interface Dermatitis

Cited by 54 publications

References 50 publications

Current translational potential and underlying molecular mechanisms of necroptosis

Current translational potential and underlying molecular mechanisms of necroptosis

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

Thymoma-associated multiorgan autoimmunity initially manifested by graft-versus-host disease–like erythroderma: Case report and possible therapeutic role of antimalarial drugs

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