IL-38 Ablation Reduces Local Inflammation and Disease Severity in Experimental Autoimmune Encephalomyelitis

Huard, Arnaud; Nam, Hoai; Frank, Ann-Christin; Sirait‐Fischer, Evelyn; Fuhrmann, Dominik C.; Hofmann, Martine; Raue, Rebecca; Palmer, Gaby; Brüne, Bernhard; Bruin, Natasja de; Weigert, Andreas

doi:10.4049/jimmunol.2000923

Cited by 18 publications

(27 citation statements)

References 38 publications

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“…We hypothesize that IL‐38 may also exert intracellular functions in keratinocytes. A recent study further demonstrated that IL‐38 promotes the production of inflammatory mediators, such as TNF‐α or TGF‐β1, in a cell‐intrinsic manner in macrophages in vitro, suggesting that IL‐38 may have intracellular effects different from its extracellular, anti‐inflammatory functions 45 …”

Section: Discussionmentioning

confidence: 99%

IL‐38 orchestrates proliferation and differentiation in human keratinocytes

Mermoud

Shutova

Díaz-Barreiro

et al. 2022

Experimental Dermatology

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Interleukin (IL)-38 is a member of the IL-1 cytokine family with reported antiinflammatory activity. The highest constitutive IL-38 expression is detected in the skin, where it is mainly produced by differentiating keratinocytes. However, little data are available regarding its biological functions. In this study, we investigated the role of IL-38 in skin physiology. We demonstrate here that dermal fibroblasts and epithelial cells of skin appendages, such as eccrine sweat glands and sebaceous glands, also express IL-38. Next, using two-and three-dimensional cell cultures, we show that endogenous expression of IL-38 correlates with keratinocyte differentiation and its ectopic overexpression inhibits keratinocyte proliferation and enhances differentiation. Accordingly, immunohistochemical analysis revealed downregulation of IL-38 in skin pathologies characterized by keratinocyte hyperproliferation, such as psoriasis and basal or squamous cell carcinoma. Finally, intracellular IL-38 can shuttle between the nucleus and the cytoplasm and its overexpression modulates the activity of the transcription regulators YAP and ID1. Our results indicate that IL-38 can act independently from immune system activation and suggest that it may affect the epidermis directly by decreasing proliferation and promoting differentiation of keratinocytes. These data suggest an important role of keratinocyte-derived IL-38 in skin homeostasis and pathologies characterized by epidermal alterations.

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Section: Discussionmentioning

confidence: 99%

IL‐38 orchestrates proliferation and differentiation in human keratinocytes

Mermoud

Shutova

Díaz-Barreiro

et al. 2022

Experimental Dermatology

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“…Many studies have shown that local inflammation and immune cell infiltration are associated with the development of skin cancer (Vahatupa et al , 2019). A recent report suggested that the absence of IL‐38 attenuates local inflammation in an experimental autoimmune encephalomyelitis model (Huard et al , 2021). To explore whether infiltration of immune cells into the skin and the alleviated skin inflammation were related to K14 Cre /+ ‐Il‐38 f / f mice with the reduction in skin carcinogenesis, we detected immune cells and the levels of pro‐inflammatory chemokines and cytokines in DMBA/TPA‐induced skin tissues.…”

Section: Resultsmentioning

confidence: 99%

“…Although several studies have explored the antiinflammatory effect of IL-38, there are some contradictions that require elucidation. Reportedly, IL-38 can promote the production of several pro-inflammatory cytokines in different cell types in response to different stimuli (Huard et al, 2021;Mora et al, 2016;van de Veerdonk et al, 2012). As an IL-1 family receptor antagonist, IL-38 has been shown to limit IL-17 production in multiple disease models (Yuan et al, 2016;Boutet et al, 2017;Han et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Interleukin‐38 promotes skin tumorigenesis in an IL‐1Rrp2‐dependent manner

et al. 2022

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Interleukin‐38 (IL‐38) is strongly associated with chronic inflammatory diseases; however, its role in tumorigenesis is poorly understood. We demonstrated that expression of IL‐38, which exhibits high expression in the skin, is downregulated in human cutaneous squamous cell carcinoma and 7,12‐dimethylbenzanthracene/12‐O‐tetradecanoyl phorbol‐13‐acetate‐induced mouse skin tumorigenesis. IL‐38 keratinocyte‐specific knockout mice displayed suppressed skin tumor formation and malignant progression. Keratinocyte‐specific deletion of IL‐38 was associated with reduced expression of inflammatory cytokines, leading to reduced myeloid cell infiltration into the local tumor microenvironment. IL‐38 is dispensable for epidermal mutagenesis, but IL‐38 keratinocyte‐specific deletion reduces proliferative gene expression along with epidermal cell proliferation and hyperplasia. Mechanistically, we first demonstrated that IL‐38 activates the c‐Jun N‐terminal kinase (JNK)/activator protein 1 signal transduction pathway to promote the expression of cancer‐related inflammatory cytokines and proliferation and migration of tumor cells in an IL‐1 receptor‐related protein 2 (IL‐1Rrp2)‐dependent manner. Our findings highlight the role of IL‐38 in the regulation of epidermal cell hyperplasia and pro‐tumorigenic microenvironment through IL‐1Rrp2/JNK and suggest IL‐38/IL‐1Rrp2 as a preventive and potential therapeutic target in skin cancer.

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“…In EAE model, IL-38 was abnormally expressed via macrophages infiltrating the spinal cord. Furthermore, the clinical score and histological markers of EAE in IL-38-deficient mice were significantly decreased, which was accompanied by decreased infiltration of inflammatory cells, for instance, macrophages, and decreased expression of inflammatory markers in the spinal cord ( Huard et al, 2021 ). This data showed that IL-38 may reduce inflammation and disease severity in EAE.…”

Section: The Function Role Of Il-38 In Autoimmune Diseasesmentioning

confidence: 99%

The Pathological Mechanism and Potential Application of IL-38 in Autoimmune Diseases

et al. 2021

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Interleukin-38 (IL-38), a new cytokine of interleukin-1 family (IL-1F), is expressed in the human heart, kidney, skin, etc. Recently, new evidence indicated that IL-38 is involved in the process of different autoimmune diseases. Autoimmune diseases are a cluster of diseases accompanied with tissue damage caused by autoimmune reactions, including rheumatoid arthritis (RA), psoriasis, etc. This review summarized the links between IL-38 and autoimmune diseases, as well as the latest knowledge about the function and regulatory mechanism of IL-38 in autoimmune diseases. Especially, this review focused on the differentiation of immune cells and explore future prospects, such as the application of IL-38 in new technologies. Understanding the function of IL-38 is helpful to shed light on the progress of autoimmune diseases.

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IL-38 Ablation Reduces Local Inflammation and Disease Severity in Experimental Autoimmune Encephalomyelitis

Cited by 18 publications

References 38 publications

IL‐38 orchestrates proliferation and differentiation in human keratinocytes

IL‐38 orchestrates proliferation and differentiation in human keratinocytes

Interleukin‐38 promotes skin tumorigenesis in an IL‐1Rrp2‐dependent manner

The Pathological Mechanism and Potential Application of IL-38 in Autoimmune Diseases

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