Publications
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Stabell, Siri Hansen; Renzi, Anastasia; Nilsen, Hogne Røed; Antonsen, Olaf Harald; Fosse, Johanna Hol & Haraldsen, Guttorm
[Show all 7 contributors for this article]
(2023).
Detection of native, activated Notch receptors in normal human apocrine-bearing skin and in hidradenitis suppurativa.
Experimental Dermatology.
ISSN 0906-6705.
33(1).
doi:
10.1111/exd.14977.
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Abstract Notch signalling has generated considerable interest as a pathogenetic factor and a drug target in a range of human diseases. The gamma‐secretase complex is crucial in the activation of Notch receptors by cleaving the intracellular domain allowing nuclear translocation. In recent years several mutations in gamma‐secretase components have been discovered in patients with familial hidradenitis suppurativa (HS). This has led to hypotheses that impaired Notch signalling could be an important driver for HS in general, not only in the monogenic variants. However, no study has examined in situ Notch activation per se in HS, and some reports with conflicting results have instead been based on expression of Notch receptors or indirect measures of Notch target gene expression. In this study we established immunostaining protocols to identify native, activated Notch receptors in human skin tissue. The ability to detect changes in Notch activation was confirmed with an ex vivo skin organ model in which signal was reduced or obliterated in tissue exposed to a gamma‐secretase inhibitor. Using these methods on skin biopsies from healthy volunteers and a general HS cohort we demonstrated for the first time the distribution of active Notch signalling in human apocrine‐bearing skin. Quantification of activated NOTCH1 & NOTCH2 revealed similar levels in non‐lesional and peri‐lesional HS to that of healthy controls, thus ruling out a general defect in Notch activation in HS patients. We did find a variable but significant reduction of activated Notch in epidermis of lesional HS with a distribution that appeared related to the extent of surrounding tissue inflammation.
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Gatti, Francesca; Mia, Sobuj; Hammarström, Clara Louise; Frerker, Nadine; Fosby, Bjarte & Wang, Junbai
[Show all 11 contributors for this article]
(2021).
Nuclear IL-33 restrains the early conversion of fibroblasts to an extracellular matrix-secreting phenotype.
Scientific Reports.
11:108(1),
p. 1–13.
doi:
10.1038/s41598-020-80509-5.
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Abstract Interleukin (IL)-33 is a cytokine that appears to mediate fibrosis by signaling via its receptor ST2 (IL-33R/IL1RL1). It is also, however, a protein that after synthesis is sorted to the cell nucleus, where it appears to affect chromatin folding. Here we describe a novel role for nuclear IL-33 in regulating the fibroblast phenotype in murine kidney fibrosis driven by unilateral ureteral obstruction. Transcriptional profiling of IL-33-deficient kidneys 24 h after ligation revealed enhanced expression of fibrogenic genes and enrichment of gene sets involved in extracellular matrix formation and remodeling. These changes relied on intracellular effects of IL-33, because they were not reproduced by treatment with a neutralizing antibody to IL-33 that prevents IL-33R/ST2L receptor signaling nor were they observed in IL-33R/ST2-deficient kidneys. To further explore the intracellular function of IL-33, we established transcription profiles of human fibroblasts, observing that knockdown of IL-33 skewed the transcription profile from an inflammatory towards a myofibroblast phenotype, reflected in higher levels of COL3A1, COL5A1 and transgelin protein, as well as lower expression levels of IL6 , CXCL8 , CLL7 and CCL8 . In conclusion, our findings suggest that nuclear IL-33 in fibroblasts dampens the initial profibrotic response until persistent stimuli, as enforced by UUO, can override this protective mechanism.
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Fjær, Roar; Marciniak, Katarzyna; Sundnes, Olav; Hjorthaug, Hanne; Sheng, Ying & Hammarström, Clara Louise
[Show all 18 contributors for this article]
(2021).
A novel somatic mutation in GNB2 provides new insights to the pathogenesis of Sturge-Weber syndrome.
Human Molecular Genetics.
ISSN 0964-6906.
30(21),
p. 1919–1931.
doi:
10.1093/hmg/ddab144.
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Sturge–Weber syndrome (SWS) is a neurocutaneous disorder characterized by vascular malformations affecting skin, eyes and leptomeninges of the brain, which can lead to glaucoma, seizures and intellectual disability. The discovery of a disease-causing somatic missense mutation in the GNAQ gene, encoding an alpha chain of heterotrimeric G-proteins, has initiated efforts to understand how G-proteins contribute to SWS pathogenesis. The mutation is predominantly detected in endothelial cells and is currently believed to affect downstream MAPK signalling. In this study of six Norwegian patients with classical SWS, we aimed to identify somatic mutations through deep sequencing of DNA from skin biopsies. Surprisingly, one patient was negative for the GNAQ mutation, but instead harbored a somatic mutation in GNB2 (NM_005273.3:c.232A>G, p.Lys78Glu), which encodes a beta chain of the same G-protein complex. The positions of the mutant amino acids in the G-protein are essential for complex reassembly. Therefore, failure of reassembly and continuous signalling is a likely consequence of both mutations. Ectopic expression of mutant proteins in endothelial cells revealed that expression of either mutant reduced cellular proliferation, yet regulated MAPK signalling differently, suggesting that dysregulated MAPK signalling cannot fully explain the SWS phenotype. Instead, both mutants reduced synthesis of Yes-associated protein (YAP), a transcriptional co-activator of the Hippo signalling pathway, suggesting a key role for this pathway in the vascular pathogenesis of SWS. The discovery of the GNB2 mutation sheds novel light on the pathogenesis of SWS and suggests that future research on targets of treatment should be directed towards the YAP, rather than the MAPK, signalling pathway.
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Lossius, Astrid Haaskjold; Sundnes, Olav; Ingham, Anna Cäcilia; Edslev, Sofie Marie; Bjørnholt, Jørgen Vildershøj & Lilje, Berit
[Show all 12 contributors for this article]
(2021).
Shifts in the Skin Microbiota after UVB Treatment in Adult Atopic Dermatitis.
Dermatology.
ISSN 1018-8665.
238(1),
p. 109–120.
doi:
10.1159/000515236.
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<b><i>Background:</i></b> The pathophysiology in atopic dermatitis (AD) is not fully understood, but immune dysfunction, skin barrier defects, and alterations of the skin microbiota are thought to play important roles. AD skin is frequently colonized with <i>Staphylococcus aureus</i> (<i>S. aureus</i>) and microbial diversity on lesional skin (LS) is reduced compared to on healthy skin. Treatment with narrow-band ultraviolet B (nb-UVB) leads to clinical improvement of the eczema and reduced abundance of <i>S. aureus</i>. However, in-depth knowledge of the temporal dynamics of the skin microbiota in AD in response to nb-UVB treatment is lacking and could provide important clues to decipher whether the microbial changes are primary drivers of the disease, or secondary to the inflammatory process. <b><i>Objectives:</i></b> To map the temporal shifts in the microbiota of the skin, nose, and throat in adult AD patients after nb-UVB treatment. <b><i>Methods:</i></b> Skin swabs were taken from lesional AD skin (<i>n</i> = 16) before and after 3 treatments of nb-UVB, and after 6–8 weeks of full-body treatment. We also obtained samples from non-lesional skin (NLS) and from the nose and throat. All samples were characterized by 16S rRNA gene sequencing. <b><i>Results:</i></b> We observed shifts towards higher diversity in the microbiota of lesional AD skin after 6–8 weeks of treatment, while the microbiota of NLS and of the nose/throat remained unchanged. After only 3 treatments with nb-UVB, there were no significant changes in the microbiota. <b><i>Conclusion:</i></b> Nb-UVB induces changes in the skin microbiota towards higher diversity, but the microbiota of the nose and throat are not altered.
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Sundnes, Olav; Ottestad, William Arne; Schjalm, Camilla; Lundbäck, Peter; Poulsen, Lars La Cour & Mollnes, Tom Eirik
[Show all 8 contributors for this article]
(2021).
Rapid systemic surge of IL-33 after severe human trauma: a prospective observational study.
Molecular medicine (Cambridge, Mass. Print).
ISSN 1076-1551.
27:29,
p. 1–10.
doi:
10.1186/s10020-021-00288-1.
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Background Alarmins are considered proximal mediators of the immune response after tissue injury. Understanding their biology could pave the way for development of new therapeutic targets and biomarkers in human disease, including multiple trauma. In this study we explored high-resolution concentration kinetics of the alarmin interleukin-33 (IL-33) early after human trauma. Methods Plasma samples were serially collected from 136 trauma patients immediately after hospital admission, 2, 4, 6, and 8 h thereafter, and every morning in the ICU. Levels of IL-33 and its decoy receptor sST2 were measured by immunoassays. Results We observed a rapid and transient surge of IL-33 in a subset of critically injured patients. These patients had more widespread tissue injuries and a greater degree of early coagulopathy. IL-33 half-life (t1/2) was 1.4 h (95% CI 1.2–1.6). sST2 displayed a distinctly different pattern with low initial levels but massive increase at later time points. Conclusions We describe for the first time early high-resolution IL-33 concentration kinetics in individual patients after trauma and correlate systemic IL-33 release to clinical data. These findings provide insight into a potentially important axis of danger signaling in humans.
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Pietka, Wojciech; Sundnes, Olav; Hammarström, Clara Louise; Zucknick, Manuela; Khnykin, Denis & Haraldsen, Guttorm
(2020).
Lack of interleukin-33 and its receptor does not prevent calcipotriol-induced atopic dermatitis-like inflammation in mice.
Scientific Reports.
10:6451,
p. 1–8.
doi:
10.1038/s41598-020-63410-z.
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Current studies addressing the influence of interleukin-33 or its receptor (IL-33R/ST2) on development of atopic dermatitis-like inflammation in mice have reported conflicting results. We compared the response in single- and double-deficient IL-33−/−/ST2−/− C57BL/6J BomTac mice in the well-established calcipotriol-induced model of atopic dermatitis. All genotypes (groups of up to 14 mice) developed atopic dermatitis-like inflammation yet we observed no biologically relevant difference between groups in gross anatomy or ear thickness. Moreover, histological examination of skin revealed no differences in mononuclear leukocyte and granulocyte infiltration nor Th2 cytokine levels (IL-4 and IL-13). Finally, skin CD45+ cells and CD3+ cells were found at similar densities across all groups. Our findings indicate that lack of interleukin-33 and its receptor ST2 does not prevent the development of AD-like skin inflammation.
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Lossius, Astrid Haaskjold; Berents, Teresa Løvold; Sætre, Frank Ove; Nilsen, Hogne Røed; Bradley, Maria & Asad, Samina
[Show all 9 contributors for this article]
(2020).
Early transcriptional changes after UVB treatment in atopic dermatitis includes inverse regulation of IL‐36γ and IL‐37.
Experimental Dermatology.
ISSN 0906-6705.
30(2),
p. 249–261.
doi:
10.1111/exd.14217.
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Phototherapy with narrow‐band Ultraviolet B (nb‐UVB) is a major therapeutic option in atopic dermatitis (AD), yet knowledge of the early molecular responses to this treatment is lacking. The objective of this study was to map the early transcriptional changes in AD skin in response to nb‐UVB treatment. Adult patients (n = 16) with AD were included in the study and scored with validated scoring tools. AD skin was irradiated with local nb‐UVB on day 0, 2 and 4. Skin biopsies were taken before and after treatment (day 0 and 7) and analysed for genome‐wide modulation of transcription. When examining the early response after three local UVB treatments, gene expression analysis revealed 77 significantly modulated transcripts (30 down‐ and 47 upregulated). Among them were transcripts related to the inflammatory response, melanin synthesis, keratinization and epidermal structure. Interestingly, the pro‐inflammatory cytokine IL‐36γ was reduced after treatment, while the anti‐inflammatory cytokine IL‐37 increased after treatment with nb‐UVB. There was also a modulation of several other mediators involved in inflammation, among them defensins and S100 proteins. This is the first study of early transcriptomic changes in AD skin in response to nb‐UVB. We reveal robust modulation of a small group of inflammatory and anti‐inflammatory targets, including the IL‐1 family members IL36γ and IL‐37, which is evident before any detectable changes in skin morphology or immune cell infiltrates. These findings provide important clues to the molecular mechanisms behind the treatment response and shed light on new potential treatment targets.
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Pietka, Wojciech; Khnykin, Denis; Bertelsen, Vibeke; Lossius, Astrid Haaskjold; Stav-Noraas, Tor Espen & Hol, Johanna
[Show all 9 contributors for this article]
(2018).
Hypo-osmotic stress drives IL-33 production in human keratinocytes - An epidermal homeostatic response.
Journal of Investigative Dermatology.
ISSN 0022-202X.
139(1),
p. 81–90.
doi:
10.1016/j.jid.2018.07.023.
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Although inflammation has traditionally been considered a response to either exogenous pathogen-associated signals or endogenous signals of cell damage, other perturbations of homeostasis, generally referred to as stress, may also induce inflammation. The relationship between stress and inflammation is, however, not well defined. Here, we describe a mechanism of IL-33 induction driven by hypo-osmotic stress in human keratinocytes and also report interesting differences when comparing the responsiveness of other inflammatory mediators. The induction of IL-33 was completely dependent on EGFR and calcium signaling, and inhibition of calcium signaling not only abolished IL-33 induction but also dramatically changed the transcriptional pattern of other cytokines upon hypo-osmotic stress. IL-33 was not secreted but instead showed nuclear sequestration, conceivably acting as a failsafe mechanism whereby it is induced by potential danger but released only upon more extreme homeostatic perturbations that result in cell death. Finally, stress-induced IL-33 was also confirmed in an ex vivo human skin model, translating this mechanism to a potential tissue-relevant signal in the human epidermis. In conclusion, we describe hypo-osmotic stress as an inducer of IL-33 expression, linking cellular stress to nuclear accumulation of a strong proinflammatory cytokine. © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
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Poulsen, Lars La Cour; Edelmann, Reidunn Jetne; Krüger, Stig; Diéguez-Hurtado, Rodrigo; Shah, Akshay & Stav-Noraas, Tor Espen
[Show all 22 contributors for this article]
(2018).
Inhibition of endothelial NOTCH1 signaling attenuates inflammation by reducing cytokine-mediated histone acetylation at inflammatory enhancers.
Arteriosclerosis, Thrombosis and Vascular Biology.
ISSN 1079-5642.
38(4),
p. 854–869.
doi:
10.1161/ATVBAHA.117.310388.
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Objective: Endothelial upregulation of adhesion molecules serves to recruit leukocytes to inflammatory sites and appears to be promoted by NOTCH1; however, current models based on interactions between active NOTCH1 and NF-κB components cannot explain the transcriptional selectivity exerted by NOTCH1 in this context. Approach and Results: Observing that Cre/Lox-induced conditional mutations of endothelial Notch modulated inflammation in murine contact hypersensitivity, we found that IL (interleukin)-1β stimulation induced rapid recruitment of RELA (v-rel avian reticuloendotheliosis viral oncogene homolog A) to genomic sites occupied by NOTCH1-RBPJ (recombination signal-binding protein for immunoglobulin kappa J region) and that NOTCH1 knockdown reduced histone H3K27 acetylation at a subset of NF-κB–directed inflammatory enhancers. Conclusions: Our findings reveal that NOTCH1 signaling supports the expression of a subset of inflammatory genes at the enhancer level and demonstrate how key signaling pathways converge on chromatin to coordinate the transition to an infla mmatory endothelial phenotype.
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Stav-Noraas, Tor Espen; Edelmann, Reidunn Jetne; Poulsen, Lars La Cour; Sundnes, Olav; Phung, Danh & Kuchler, Axel Matthias
[Show all 11 contributors for this article]
(2017).
Endothelial IL-33 expression is augmented by adenoviral activation of the DNA damage machinery.
Journal of Immunology.
ISSN 0022-1767.
198(8),
p. 3318–3325.
doi:
10.4049/jimmunol.1600054.
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IL-33, required for viral clearance by cytotoxic T cells, is generally expressed in vascular endothelial cells in healthy human tissues. We discovered that endothelial IL-33 expression was stimulated as a response to adenoviral transduction. This response was dependent on MRE11, a sensor of DNA damage that can also be activated by adenoviral DNA, and on IRF1, a transcriptional regulator of cellular responses to viral invasion and DNA damage. Accordingly, we observed that endothelial cells responded to adenoviral DNA by phosphorylation of ATM and CHK2 and that depletion or inhibition of MRE11, but not depletion of ATM, abrogated IL-33 stimulation. In conclusion, we show that adenoviral transduction stimulates IL-33 expression in endothelial cells in a manner that is dependent on the DNA-binding protein MRE11 and the antiviral factor IRF1 but not on downstream DNA damage response signaling. This research has been published in the Journal of Immunology. © 2017 American Association of Immunologists
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Gundersen, Mona Dixon; Goll, Rasmus; Hol, Johanna; Olsen, Trine; Rismo, Renathe & Sørbye, Sveinung Wergeland
[Show all 9 contributors for this article]
(2016).
Loss of interleukin 33 expression in colonic crypts - a potential marker for disease remission in ulcerative colitis.
Scientific Reports.
6.
doi:
10.1038/srep35403.
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Interleukin 33 (IL-33) is a cytokine preferentially elevated in acute ulcerative colitis (UC), inferring a role in its pathogenesis. The role of IL-33 in intestinal inflammation is incompletely understood, with both pro-inflammatory and regulatory properties described. There are also conflicting reports on cellular sources and subcellular location of IL-33 in the colonic mucosa, justifying a closer look at IL-33 expression in well-defined clinical stages of UC. A total of 50 study participants (29 UC patients and 21 healthy controls) were included from a prospective cohort of inflammatory bowel disease patients treated to disease remission with infliximab, a tumour necrosis factor alpha (TNF) inhibitor. To our knowledge this is the first study examining mucosal IL-33 expression before and after anti-TNF therapy. In colonic mucosal biopsies we found a 3-fold increase in IL-33 gene expression comparing acute UC to healthy controls (p < 0.01). A significant reduction of IL33 between acute UC and disease remission was observed when TNF normalised in the mucosa (p = 0.02). Immunostaining revealed IL-33 in the nuclei of epithelial cells of scattered colonic crypts in acute disease, while at disease remission, IL-33 was undetectable, a novel finding suggesting that enterocyte-derived IL-33 is induced and maintained by inflammatory mediators.
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Tveita, Anders; Schjesvold, Fredrik Hellem; Sundnes, Olav; Haabeth, Ole Audun; Haraldsen, Guttorm & Bogen, Bjarne
(2014).
Indirect CD4+ T-cell-mediated elimination of MHC II(NEG) tumor cells is spatiallyrestricted and fails to prevent escape of antigen-negative cells.
European Journal of Immunology.
ISSN 0014-2980.
44(9),
p. 2625–2637.
doi:
10.1002/eji.201444659.
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KIM, Ashley S & Sundnes, Olav
(2025).
Childhood Linear IgA Dermatosis Successfully Treated with the Combination of Dapsone and Sulfasalazine.
Case Reports in Dermatology.
ISSN 1662-6567.
17(1),
p. 185–190.
doi:
10.1159/000546155.
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Alfonso, Jose Hernan; Bassarova, Assia Vassileva; Endre, Kim Magnus Advocaat; Sundnes, Olav & Lossius, Astrid Haaskjold
(2024).
Generalised pustular psoriasis triggered by monkeypox vaccination successfully treated with spesolimab.
JEADV Clinical Practice.
3(5).
doi:
10.1002/jvc2.493.
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Sundnes, Olav; Khnykin, Denis & Haraldsen, Guttorm
(2013).
Cellular expression of the alarmin IL-33 in acute skin inflammation.
Journal of Investigative Dermatology.
ISSN 0022-202X.
133,
p. S52–S52.
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Schjesvold, Fredrik Hellem; Tveita, Anders; Sundnes, Olav; Haraldsen, Guttorm & Bogen, Bjarne
(2013).
CD4+T cell-mediated protection against tumors: no bystander killing.
Journal of Immunology.
ISSN 0022-1767.
190.
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Published
Aug. 21, 2020 2:10 PM
- Last modified
Aug. 24, 2020 12:28 PM
