OVOL1 Regulates Psoriasis-Like Skin Inflammation and Epidermal Hyperplasia

Sun, Peng; Vu, Remy; Dragan, Morgan; Haensel, Daniel; Gutierrez, Guadalupe; Nguyen, Quy; Greenberg, Elyse Noelani; Chen, Zeyu; Wu, Jie; Atwood, Scott X.; Pearlman, Eric; Shi, Yujun; Wang, Han; Kessenbrock, Kai; Dai, Xing

doi:10.1016/j.jid.2020.10.025

Cited by 13 publications

(17 citation statements)

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“…OVOL1 has been previously identified as a susceptibility locus for inflammatory skin diseases such as atopic dermatitis and acne (Paternoster et al , 2011; Hirota et al , 2012; Marenholz et al , 2015), and Ovol1 plays a protective role in psoriasis‐like skin inflammation (Sun et al , 2021). Importantly, our work identifies a number of inflammatory genes as direct targets of Ovol1/2, and aberrant immune activation in skin as a likely direct cellular response to Ovol1/2 deletion in the epidermis.…”

Section: Discussionmentioning

confidence: 99%

“…Ovol1 and Ovol2 floxed (f) alleles were previously described (Unezaki et al , 2007; Haensel et al , 2019; Dragan et al , 2022) and intercrossed to generate Ovol1 f/f ; Ovol2 f/f breeders. Ovol1 f/f ; Ovol2 f/f females were crossed with Ovol1 +/− ; Ovol2 +/− ; K14 ‐CreER mice (Vasioukhin et al , 1999; Haensel et al , 2019; Sun et al , 2021) to generate Ovol1 f/− ; Ovol2 fl/− ; K14 ‐CreER (iDKO) mice that were injected with 75 mg tamoxifen/kg body weight for 5 consecutive days at 7 weeks old. All controls used are sex‐matched littermates.…”

Section: Methodsmentioning

confidence: 99%

“…Ovol1 is normally expressed in differentiating epidermal keratinocytes, and germline loss of Ovol1 causes embryonic epidermal hyperproliferation and a transient delay in barrier acquisition (Nair et al , 2006; Teng et al , 2007). In adult stage, Ovol1 ‐deficient mice are more susceptible to imiquimod‐induced psoriasis‐like inflammation, but otherwise do not show remarkable perturbation in skin homeostasis (Sun et al , 2021; Dragan et al , 2022). Ovol2 is normally expressed in epidermal basal stem/progenitor cells, and Ovol2 ‐deficient mice show delayed wound closure with compromised directional migration while their epidermal development and homeostasis remain largely intact (Haensel et al , 2019).…”

Section: Introductionmentioning

confidence: 99%

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Ovol1/2 loss‐induced epidermal defects elicit skin immune activation and alter global metabolism

Dragan

Chen

et al. 2023

EMBO Reports

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Skin epidermis constitutes the outer permeability barrier that protects the body from dehydration, heat loss, and myriad external assaults. Mechanisms that maintain barrier integrity in constantly challenged adult skin and how epidermal dysregulation shapes the local immune microenvironment and whole‐body metabolism remain poorly understood. Here, we demonstrate that inducible and simultaneous ablation of transcription factor‐encoding Ovol1 and Ovol2 in adult epidermis results in barrier dysregulation through impacting epithelial‐mesenchymal plasticity and inflammatory gene expression. We find that aberrant skin immune activation then ensues, featuring Langerhans cell mobilization and T cell responses, and leading to elevated levels of secreted inflammatory factors in circulation. Finally, we identify failure to gain body weight and accumulate body fat as long‐term consequences of epidermal‐specific Ovol1/2 loss and show that these global metabolic changes along with the skin barrier/immune defects are partially rescued by immunosuppressant dexamethasone. Collectively, our study reveals key regulators of adult barrier maintenance and suggests a causal connection between epidermal dysregulation and whole‐body metabolism that is in part mediated through aberrant immune activation.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ovol1/2 loss‐induced epidermal defects elicit skin immune activation and alter global metabolism

Dragan

Chen

et al. 2023

EMBO Reports

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“…OVOL1 might be the missing link between FLG deficiency and abnormal lipid metabolism in AD. Indeed, OVOL1 controls the expression of FLG and a recent study revealed that lipid metabolism is the most altered metabolic pathway, with the notable upregulation of PPARδ, in OVOL1 knock-out mice treated with imiquimod to induce psoriasislike inflammation [181]. We have recently reported a key role of PPARδ signaling in the pathogenesis of AD and potentially of psoriasis, by up-regulating peroxisomal ß-oxidation via ACOX1, which contributes to shortening of SC lipid species, thereby initiating or perpetuating epidermal barrier impairment in AD [74].…”

Section: Discussionmentioning

confidence: 99%

Atopic Dermatitis: The Fate of the Fat

Pavel

Blunder

Moosbrugger‐Martinz

et al. 2022

IJMS

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Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease in which dry and itchy skin may develop into skin lesions. AD has a strong genetic component, as children from parents with AD have a twofold increased chance of developing the disease. Genetic risk loci and epigenetic modifications reported in AD mainly locate to genes involved in the immune response and epidermal barrier function. However, AD pathogenesis cannot be fully explained by (epi)genetic factors since environmental triggers such as stress, pollution, microbiota, climate, and allergens also play a crucial role. Alterations of the epidermal barrier in AD, observed at all stages of the disease and which precede the development of overt skin inflammation, manifest as: dry skin; epidermal ultrastructural abnormalities, notably anomalies of the lamellar body cargo system; and abnormal epidermal lipid composition, including shorter fatty acid moieties in several lipid classes, such as ceramides and free fatty acids. Thus, a compelling question is whether AD is primarily a lipid disorder evolving into a chronic inflammatory disease due to genetic susceptibility loci in immunogenic genes. In this review, we focus on lipid abnormalities observed in the epidermis and blood of AD patients and evaluate their primary role in eliciting an inflammatory response.

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“…Psoriasis is a common hyperplastic chronic inflammatory skin disease characterized by persistent inflammation resulting in the parakeratosis, abnormal differentiation, and hyperplasia of epidermal keratinocytes. [1][2][3] The inflammatory milieu activates signaling pathways to induce keratinocyte proliferation and differentiation depending on different nuclear transcription factors, such as signal transducer and activator of transcription (STAT)-1, 4 STAT-3, 5,6 nuclear factor-κB (NF-κB), 7 MAF bZIP transcription factor B, 8 interferon regulated factor-1 (IRF-1), 9 ovo-like transcriptional repressor 1, 10,11 grainyhead-like (GRHL), 12 and LIM-only protein 4 (LMO4). LMO4, a member of the LMO family, predominantly regulates the proliferation and differentiation of epithelial cells during embryogenesis.…”

Section: Introductionmentioning

confidence: 99%

Pro‐inflammatory cytokine IL‐6 regulates LMO4 expression in psoriatic keratinocytes via AKT/STAT3 pathway

Tu,

Wei,

Xiang

et al. 2023

Immunity Inflam & Disease

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The transcription factor LIM‐only protein 4 (LMO4) is overexpressed in the psoriatic epidermis and regulates keratinocyte proliferation and differentiation. High LMO4 expression levels are induced by interleukin‐23 (IL‐23) to activate the AKT/STAT3 signaling pathway. Interleukin‐6 (IL‐6) is mainly involved in regulating T cell functions and development in patients with psoriasis. However, whether LMO4 expression is regulated by IL‐6 remains unclear. Therefore, the purpose of this study is to explore the role and molecular mechanisms of IL‐6 in regulating LMO4 expression. The interleukin‐6 (IL‐6) levels in human plasma were determined using a chemiluminescence immunoassay system. A psoriasis‐like mouse model was established using imiquimod induction. Epidermal keratinocytes (HaCaT) were cultured in defined keratinocyte‐serum‐free medium and stimulated by IL‐6 alone or with inhibitors. The proteins of interest were detected using western blot analysis, immunofluorescence, and immunohistochemistry. The 5‐ethynyl‐2′‐deoxyuridine assay was used to detect cell proliferation. The results revealed that IL‐6 levels were markedly increased in the plasma of patients with psoriasis, compared to healthy control. The high expression of LMO4 was consistent with high levels of IL‐6, p‐AKT, and p‐STAT3 in the lesions of both psoriasis patients and imiquimod‐induced psoriasis‐like mice. IL‐6 activates the AKT/STAT3 signaling pathway, followed by LMO4 high‐expression in HaCaT cells. IL‐6 induces HaCaT proliferation and differentiation via AKT/STAT3 signaling pathway activation. We think that the high expression of LMO4 in psoriatic keratinocytes requires IL‐6 to activate the AKT/STAT3 signaling pathway and leads to epidermal keratinocytes abnormal proliferation and differentiation.

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OVOL1 Regulates Psoriasis-Like Skin Inflammation and Epidermal Hyperplasia

Cited by 13 publications

References 47 publications

Ovol1/2 loss‐induced epidermal defects elicit skin immune activation and alter global metabolism

Ovol1/2 loss‐induced epidermal defects elicit skin immune activation and alter global metabolism

Atopic Dermatitis: The Fate of the Fat

Pro‐inflammatory cytokine IL‐6 regulates LMO4 expression in psoriatic keratinocytes via AKT/STAT3 pathway

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