A model of skin inflammation in humans leads to a rapid and reproducible increase in the interferon response signature: a potential translational model for drug development

Dickson, Marion C.; Ludbrook, Valerie J.; Perry, Hayley; Wilson, P. David; Garthside, Sam J.; Binks, Michael

doi:10.1007/s00011-015-0795-z

Cited by 10 publications

(14 citation statements)

References 30 publications

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“…CXCL10, MX‐A, ICAM‐1, and hBD‐2 were all statistically significantly upregulated in the skin of subjects treated with IMQ for 48 hours and 72 hours in combination with TS and to a lesser extent in the non‐TS cohort (only for hBD‐2) compared with vehicle, which is concordant with the molecular findings of Dickson et al . This reflects the intermediate phase response of IMQ (24–72 hours) where activation of the innate as well as adaptive immune system occurs, featuring infiltration of neutrophils, lymphocytes, and macrophages, as described in a recent review of the murine translational IMQ skin inflammation models .…”

Section: Discussionsupporting

confidence: 88%

“…This reflects the intermediate phase response of IMQ (24–72 hours) where activation of the innate as well as adaptive immune system occurs, featuring infiltration of neutrophils, lymphocytes, and macrophages, as described in a recent review of the murine translational IMQ skin inflammation models . CXCL10, a chemokine that is highly expressed when keratinocytes are activated in inflamed skin, is regulated by T cells and found in psoriasis and other autoimmune diseases, which corresponds with the findings in our clinically induced skin inflammation . Upregulation of MX‐A, a downstream mediator of interferons, reflects the activation of plasmacytoid dendritic cells (pDCs), which play a major role in the pathophysiology of psoriasis .…”

Section: Discussionsupporting

confidence: 82%

“…Only limited aspects of the molecular signature of psoriasis were observed . Other studies in healthy volunteers characterized the model by either solely focusing on biopsy biomarkers or only systemic effects after high topical doses of IMQ . Acute and rapid IMQ‐induced inflammation models in healthy volunteers with detailed characterization have not yet been reported.…”

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confidence: 99%

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Comprehensive, Multimodal Characterization of an Imiquimod‐Induced Human Skin Inflammation Model for Drug Development

Kolk

Assil

Rijneveld

et al. 2018

Clinical Translational Sci

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Imiquimod (IMQ) is often used as a topical challenge agent to provoke local skin inflammation. The objective of this study was to develop and refine a rapid, temporary, and reversible human skin inflammation model with IMQ for application in clinical drug development. A randomized, vehicle‐controlled, open‐label, dose‐ranging study was conducted in 16 healthy male subjects. IMQ (5 mg) was applied once daily for 72 hours under occlusion to intact skin (n = 8) or tape stripped (TS) skin (n = 8). Although IMQ alone induced limited effects, TS+IMQ treatment showed larger responses in several domains, including erythema and perfusion (P < 0.0001), mRNA expression of inflammatory markers (P < 0.01), and inflammatory cell influx compared with vehicle. In conclusion, a rapid, human IMQ skin inflammation challenge model was successfully developed with a clear benefit of TS prior to IMQ application. Future interaction studies will enable proof‐of‐pharmacology of novel compounds targeting the innate immune system.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 82%

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confidence: 99%

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Comprehensive, Multimodal Characterization of an Imiquimod‐Induced Human Skin Inflammation Model for Drug Development

Kolk

Assil

Rijneveld

et al. 2018

Clinical Translational Sci

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“…The ex vivo qRT-PCR measurements showed a change in gene expression for IP-10 and TGF-β, both modulators that contribute to the induction of Langerhans cells and dendritic cell maturation as well as the positioning of CXCR3-positive T cells in the skin [16,23,24,36]. IP-10 together with IFN has already been described as an important cytokine induced by barrier disruption methods like tape stripping [37,38]. A 2-phased reaction of skin to barrier disruption has been described [39].…”

Section: Discussionmentioning

confidence: 99%

Physiological and Molecular Effects of in vivo and ex vivo Mild Skin Barrier Disruption

Pfannes

Weiss²,

Hadam³

et al. 2018

Skin Pharmacol Physiol

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The success of topically applied treatments on skin relies on the efficacy of skin penetration. In order to increase particle or product penetration, mild skin barrier disruption methods can be used. We previously described cyanoacrylate skin surface stripping as an efficient method to open hair follicles, enhance particle penetration, and activate Langerhans cells. We conducted ex vivo and in vivo measurements on human skin to characterize the biological effect and quantify barrier disruption-related inflammation on a molecular level. Despite the known immunostimulatory effects, this barrier disruption and hair follicle opening method was well accepted and did not result in lasting changes of skin physiological parameters, cytokine production, or clinical side effects. Only in ex vivo human skin did we find a discrete increase in IP-10, TGF-β, IL-8, and GM-CSF mRNA. The data underline the safety profile of this method and demonstrate that the procedure per se does not cause substantial inflammation or skin damage, which is also of interest when applied to non-invasive sampling of biomarkers in clinical trials.

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“…These data support the idea that miR‐31 may play a crucial role in the biology of rodent hair follicles. miR‐31 is also upregulated in skin diseases such as psoriasis and squamous cell carcinoma (SCC), indicating that miR‐31 plays a role in the response to restoring epidermal homeostasis or driving hyperproliferation . Interestingly, in other cell types miR‐31 can inhibit proliferation.…”

Section: Introductionmentioning

confidence: 99%

The major miR‐31 target genes STK40 and LATS2 and their implications in the regulation of keratinocyte growth and hair differentiation

Luan

Shi

et al. 2017

Experimental Dermatology

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Emerging evidence indicates that even subtle changes in the expression of key genes of signalling pathways can have profound effects. MicroRNAs (miRNAs) are masters of subtlety and generally have only mild effects on their target genes. The microRNA miR-31 is one of the major microRNAs in many cutaneous conditions associated with activated keratinocytes, such as the hyperproliferative diseases psoriasis, non-melanoma skin cancer and hair follicle growth. miR-31 is a marker of the hair growth phase, and in our miR-31 transgenic mouse model it impairs the function of keratinocytes. This leads to aberrant proliferation, apoptosis, and differentiation that results in altered hair growth, while the loss of miR-31 leads to increased hair growth. Through in vitro and in vivo studies, we have defined a set of conserved miR-31 target genes, including LATS2 and STK40, which serve as new players in the regulation of keratinocyte growth and hair follicle biology. LATS2 can regulate growth of keratinocytes and we have identified a function of STK40 that can promote the expression of key hair follicle programme regulators such as HR, DLX3 and HOXC13.

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A model of skin inflammation in humans leads to a rapid and reproducible increase in the interferon response signature: a potential translational model for drug development

Abstract: Results suggest that IFN signalling is important in these translational models and novel miRNA may be new targets in the treatment of IFN associated skin disease.

Cited by 10 publications

References 30 publications

Comprehensive, Multimodal Characterization of an Imiquimod‐Induced Human Skin Inflammation Model for Drug Development

Comprehensive, Multimodal Characterization of an Imiquimod‐Induced Human Skin Inflammation Model for Drug Development

Physiological and Molecular Effects of in vivo and ex vivo Mild Skin Barrier Disruption

The major miR‐31 target genes STK40 and LATS2 and their implications in the regulation of keratinocyte growth and hair differentiation

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