IL-37 Expression Is Downregulated in Lesional Psoriasis Skin

Rønholt, Kirsten; Nielsen, Ane Langkilde-Lauesen; Johansen, Claus; Vestergaard, Christian; Fauerbye, Astrid; López-Vales, Rubén; Dinarello, Charles A.; Iversen, Lars

doi:10.4049/immunohorizons.2000083

Cited by 23 publications

(20 citation statements)

References 24 publications

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“…The most prominent reduction in IL-37 were observed in chronic AD lesional skin. Interestingly, it has previously been demonstrated that IL-37 expression is also reduced in psoriatic skin specimens (24). Owing to its anti-inflammatory properties, reduced levels of IL-37 might impact the inflammatory milieu of the skin microenvironment.…”

Section: Discussionmentioning

confidence: 98%

Transcriptomic Analysis of Healthy and Atopic Dermatitis Samples Reveals the Role of IL-37 in Human Skin

et al. 2021

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Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects up to one in five children and millions of adults in developed countries. Clinically, AD skin lesions manifest as subacute and/or chronic lichenified eczematous plaques, which are often intensely pruritic and prone to secondary bacterial and viral infections. Despite the emergence of novel therapeutic agents, treatment options and outcomes for AD remain suboptimal. An improved understanding of AD pathogenesis may help improve patient outcomes. Dysregulated T h 2-polarized skin inflammation and impaired skin barrier function interact to drive AD pathogenesis; however, much remains to be understood about the molecular mechanisms underlying this interplay. The current study used published clinical trial datasets to define a skin-related AD gene signature. This meta-analysis revealed significant reductions in IL1F7 transcripts (encodes IL-37) in AD patient samples. Reduced IL1F7 correlated with lower transcripts for key skin barrier function genes in the epidermal differentiation complex. Immunohistochemical analysis of normal (healthy) human skin specimens and an in vitro three-dimensional human skin model localized IL-37 protein to the epidermis. In comparison with normal human skin, IL-37 levels were decreased in AD patient skin. Addition of T h 2 cytokines to the aforementioned in vitro three-dimensional skin model recapitulates key aspects of AD skin and was sufficient to reduce epidermal IL-37 levels. Image analysis also indicated close relationship between epidermal IL-37 and skin epidermal differentiation complex proteins. These findings suggest IL-37 is intimately linked to normal keratinocyte differentiation and barrier function and implicates IL-37 as a potential biomarker and therapeutic target for AD. ImmunoHorizons, 2021, 5: 830-843.

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Section: Discussionmentioning

confidence: 98%

Transcriptomic Analysis of Healthy and Atopic Dermatitis Samples Reveals the Role of IL-37 in Human Skin

et al. 2021

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“…Similarly, injection of a human IL-37b expression vector reduced disease severity, cytokine production and skin mast cell density in a keratin 14 VEGF-A-transgenic mouse model of psoriasis (183). Finally, a single intradermal injection of recombinant mature human IL-37b tended to reduce epidermal thickness, although it did not decrease inflammatory cytokine expression in a model of Aldara (5% IMQ)-induced skin inflammation (236).…”

Section: Il-37 In Human Inflammatory Skin Diseasesmentioning

confidence: 94%

“…Several studies showed reduced IL37 mRNA expression in lesional psoriatic skin as compared to non-lesional and control skin (127,203,235,236). One study further indicated that successful treatment of psoriasis patients with the Janus kinase (JAK) inhibitor tofacitinib restored IL37 expression levels in the skin (237).…”

Section: Il-37 Expression Activity and Signalingmentioning

confidence: 99%

IL-1 Family Antagonists in Mouse and Human Skin Inflammation

et al. 2021

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Interleukin (IL)-1 family cytokines initiate inflammatory responses, and shape innate and adaptive immunity. They play important roles in host defense, but excessive immune activation can also lead to the development of chronic inflammatory diseases. Dysregulated IL-1 family signaling is observed in a variety of skin disorders. In particular, IL-1 family cytokines have been linked to the pathogenesis of psoriasis and atopic dermatitis. The biological activity of pro-inflammatory IL-1 family agonists is controlled by the natural receptor antagonists IL-1Ra and IL-36Ra, as well as by the regulatory cytokines IL-37 and IL-38. These four anti-inflammatory IL-1 family members are constitutively and highly expressed at steady state in the epidermis, where keratinocytes are a major producing cell type. In this review, we provide an overview of the current knowledge concerning their regulatory roles in skin biology and inflammation and their therapeutic potential in human inflammatory skin diseases. We further highlight some common misunderstandings and less well-known observations, which persist in the field despite recent extensive interest for these cytokines.

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“…The therapeutic efficacy of anti-TNF-α/IL-23/IL-17A biologics for psoriasis suggests that the TNF-α/IL-23/IL-17A axis plays a central role in its pathogenesis ( 11 ). Although the precise role of IL-37 in the development of psoriasis remains unclear, intradermal injection of recombinant human IL-37 into a murine imiquimod-induced psoriasis model reportedly demonstrated a trend toward a protective effect ( 12 ). It has also been reported that IL-37 expression is markedly downregulated in biopsies from lesional psoriasis human skin compared with the level in paired samples of non-lesional skin ( 12 , 13 ).…”

Section: Introductionmentioning

confidence: 99%

“…Although the precise role of IL-37 in the development of psoriasis remains unclear, intradermal injection of recombinant human IL-37 into a murine imiquimod-induced psoriasis model reportedly demonstrated a trend toward a protective effect ( 12 ). It has also been reported that IL-37 expression is markedly downregulated in biopsies from lesional psoriasis human skin compared with the level in paired samples of non-lesional skin ( 12 , 13 ). These findings suggest that IL-37 may have potential to prevent the development of psoriasis, in addition to AD.…”

Section: Introductionmentioning

confidence: 99%

Natural Compounds Tapinarof and Galactomyces Ferment Filtrate Downregulate IL-33 Expression via the AHR/IL-37 Axis in Human Keratinocytes

et al. 2022

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Interleukin (IL)-37 suppresses systemic and local inflammation. It is expressed in the epidermis, the external layer of the skin, and is decreased in inflammatory skin diseases including atopic dermatitis (AD) and psoriasis. Therefore, an agent applied topically on the skin that can increase IL-37 could be promising for treating AD and psoriasis; however, the mechanism regulating IL-37 remains largely unknown. Given that IL-37 expression is induced in differentiated keratinocytes, a major component of the epidermis, and that activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, promotes keratinocyte differentiation, we hypothesized that AHR might be involved in the IL-37 expression in human keratinocytes. We analyzed normal epidermal human keratinocytes (NHEKs) treated with tapinarof and Galactomyces ferment filtrate (GFF), which are potent AHR modulators. We found that tapinarof and GFF upregulated IL-37 in NHEKs, which was canceled by the knockdown of AHR using siRNA transfection, indicating that AHR mediates IL-37 expression in NHEKs. Furthermore, we found that the knockdown of IL-37 resulted in the upregulation of IL-33, an alarmin cytokine with crucial roles in the pathogenesis of AD and psoriasis. These findings suggest that IL-37 negatively regulates IL-33 expression in NHEKs. Finally, we examined whether tapinarof and GFF treatment modulates IL-33 expression in NHEKs. Such treatment inhibited IL-33 expression, which was partially reversed by the knockdown of either AHR or IL-37. Taken together, our findings provide the first evidence that tapinarof and GFF could have potential to prevent IL-33-overexpressing disorders such as AD and psoriasis via the AHR/IL-37 axis.

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IL-37 Expression Is Downregulated in Lesional Psoriasis Skin

Cited by 23 publications

References 24 publications

Transcriptomic Analysis of Healthy and Atopic Dermatitis Samples Reveals the Role of IL-37 in Human Skin

Transcriptomic Analysis of Healthy and Atopic Dermatitis Samples Reveals the Role of IL-37 in Human Skin

IL-1 Family Antagonists in Mouse and Human Skin Inflammation

Natural Compounds Tapinarof and Galactomyces Ferment Filtrate Downregulate IL-33 Expression via the AHR/IL-37 Axis in Human Keratinocytes

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