Epidermal ADAM17 maintains the skin barrier by regulating EGFR ligand–dependent terminal keratinocyte differentiation

Franzke, Claus Werner; Cobzaru, Cristina; Triantafyllopoulou, Antigoni; Löffek, Stefanie; Horiuchi, Keisuke; Threadgill, David W.; Kurz, Thomas; Rooijen, Nico van; Bruckner‐Tuderman, Leena; Blobel, Carl P.

doi:10.1084/jem.20112258

Cited by 166 publications

(107 citation statements)

References 69 publications

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“…Moreover it delays apoptosis during early differentiation in suprabasal keratinocytes that have lost their interaction with the matrix89. However, EGFR-ligands are also abundant in differentiated epidermis and there are several evidences that EGFR signalling contributes to terminal keratinocyte differentiation and skin barrier formation10111213. EGFR deficiency causes defects in hair follicle development and immature epidermal differentiation with inflammatory skin reactions in both mice and humans14151617.…”

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confidence: 99%

ADAM17/EGFR axis promotes transglutaminase-dependent skin barrier formation through phospholipase C γ1 and protein kinase C pathways

Wolf

Qian

Brooke

et al. 2016

Sci Rep

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The vitally important skin barrier is formed by extensive cross-linking activity of transglutaminases (TGs) during terminal epidermal differentiation. We have previously shown that epidermal deficiency of a disintegrin and metalloproteinase 17 (ADAM17), the principal EGFR ligand sheddase, results in postnatal skin barrier defects in mice due to impeded TG activity. However, the mechanism by which ADAM17/EGFR signalling maintains TG activity during epidermal differentiation remains elusive. Here we demonstrate that ADAM17-dependent EGFR signalling promotes TG activity in keratinocytes committed to terminal differentiation by direct induction of TG1 expression. Restored TG1 expression of EGF-stimulated differentiated Adam17−/− keratinocytes was strongly repressed by inhibitors for PLCγ1 or protein kinase C (PKC) pathways, while treatment with the PKC stimulator 12-O-tetradecanoylphorbol-13-acetate restored TG activity in the epidermis of keratinocyte-specific Adam17−/− (AD17ΔKC) mice. Further investigations emphasized the expression of PKCη, a mediator of TGM1 transcription, to be sensitive to EGFR activation. In agreement, topical skin application of cholesterol sulfate, an activator of PKCη, significantly improved TG activity in epidermis of AD17ΔKC mice. Our results suggest ADAM17/EGFR-driven PLCγ1 and PKC pathways as important promoters of TG1 expression during terminal keratinocyte differentiation. These findings may help to identify new therapeutic targets for inflammatory skin diseases related to epidermal barrier defects.

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confidence: 99%

ADAM17/EGFR axis promotes transglutaminase-dependent skin barrier formation through phospholipase C γ1 and protein kinase C pathways

Wolf

Qian

Brooke

et al. 2016

Sci Rep

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“…IEC proliferation is critical for adaptive growth after intestinal injury/inflammation (47,48), and EGFR/ErbB is a major mediator of these IEC responses (44,48,49). In the DSS colitis model, hypomorphic Egfr mice and ErbB ligand-deficient mice display exacerbated intestinal inflammation (50,51), whereas more recent studies using different IEC-ErbB KO mice have shown that all four ErbB receptors contribute, in various degrees, to protection against DSS-induced colitis (19,24,26,45). Evidence that ADAM17 is an upstream regulator of EGFR/ErbB signaling in the DSS colitis model comes from analysis of hypomorphic Adam17 mice under continuous exposure to low-dose DSS (21,23).…”

Section: Discussionmentioning

confidence: 99%

“…However, the ability of ADAM17 to regulate ectodomain processing of additional substrates was clearly demonstrated by the fact that Tace ⌬Zn/⌬Zn mice display perinatal lethality, whereas TNF-␣-deficient mice or mice lacking TNFRs are viable and fertile (11,12). The developmental defects observed in Tace ⌬Zn/⌬Zn mice are characteristic of EGFR-deficient (Egfr Ϫ/Ϫ ) mice (14,15), and the defects in skin, heart valve, and mammary gland development have been directly attributed to the inability to process and activate specific EGFR ligands (16)(17)(18)(19).…”

Section: Micementioning

confidence: 99%

Loss of ADAM17-Mediated Tumor Necrosis Factor Alpha Signaling in Intestinal Cells Attenuates Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

Yang

Tsai

Xiao

et al. 2015

Molecular and Cellular Biology

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e Total parenteral nutrition (TPN) is commonly used clinically to sustain patients; however, TPN is associated with profound mucosal atrophy, which may adversely affect clinical outcomes. Using a mouse TPN model, removing enteral nutrition leads to decreased crypt proliferation, increased intestinal epithelial cell (IEC) apoptosis and increased mucosal tumor necrosis factor alpha (TNF-␣) expression that ultimately produces mucosal atrophy. Upregulation of TNF-␣ signaling plays a central role in mediating TPN-induced mucosal atrophy without intact epidermal growth factor receptor (EGFR) signaling. Currently, the mechanism and the tissue-specific contributions of TNF-␣ signaling to TPN-induced mucosal atrophy remain unclear. ADAM17 is an ectodomain sheddase that can modulate the signaling activity of several cytokine/growth factor receptor families, including the TNF-␣/TNF receptor and ErbB ligand/EGFR pathways. Using TPN-treated IEC-specific ADAM17-deficient mice, the present study demonstrates that a loss of soluble TNF-␣ signaling from IECs attenuates TPN-induced mucosal atrophy. Importantly, this response remains dependent on the maintenance of functional EGFR signaling in IECs. TNF-␣ blockade in wild-type mice receiving TPN confirmed that soluble TNF-␣ signaling is responsible for downregulation of EGFR signaling in IECs. These results demonstrate that ADAM17-mediated TNF-␣ signaling from IECs has a significant role in the development of the proinflammatory state and mucosal atrophy observed in TPN-treated mice.A lthough total parenteral nutrition (TPN) is an essential therapy for patients who cannot tolerate enteral nutrition, there are numerous and significant clinical sequelae associated with TPN treatment (1). These clinical complications, which include altered immunological responses, hepatic dysfunction, metabolic derangements, endotoxemia, bacterial infections, and sepsis, can delay or make it difficult to wean patients back onto enteral nutrition. Several studies have indicated that early TPN administration in critically ill patients is associated with worsened clinical outcomes and increased rates of septicemia, often from enterically derived organisms (1, 2). These issues clearly highlight that a more detailed understanding of the underlying mechanisms of TPN-related intestinal complications is needed both to improve the selection and administration of TPN to patients and for the development of new therapeutic options for patients dependent on TPN.The mouse model of TPN represents an ideal system to study signal transduction pathways contributing to mucosal atrophy without acute inflammatory changes or intestinal epithelial cell (IEC) destruction seen in other intestinal injury/inflammation models. The removal of enteral nutrition is associated with decreased crypt proliferation, increased IEC apoptosis, a loss of epithelial barrier function (EBF), and altered enteric microbiota, resulting in a mild proinflammatory state and mucosal atrophy (1). Previous studies have shown that upregulation of tumor...

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“…The classical skin tumor promoter, TPA, has been shown to induce skin tumorigenesis via activation of various inflammatory pathways. A recent study demonstrated that mice overexpressing TACE shows augmented dermal fibrosis and inflammation in response to TPA 25 , however, mice lacking TACE in keratinocytes develops spontaneous dermal inflammation 26,27 . The present study was designed to demonstrate the effect of a selective TACE inhibitor on skin inflammation and tumorigenesis induced by TPA in mice.…”

Section: Discussionmentioning

confidence: 99%

Chemopreventive effect of a novel, selective TACE inhibitor on DMBA- and TPA-induced skin carcinogenesis

Sharma¹,

Mohapatra²,

Argade

et al. 2014

Immunopharmacology and Immunotoxicology

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Epidermal ADAM17 maintains the skin barrier by regulating EGFR ligand–dependent terminal keratinocyte differentiation

Abstract: EGFR requires ADAM17 activity to preserve skin barrier homeostasis.

Cited by 166 publications

References 69 publications

ADAM17/EGFR axis promotes transglutaminase-dependent skin barrier formation through phospholipase C γ1 and protein kinase C pathways

ADAM17/EGFR axis promotes transglutaminase-dependent skin barrier formation through phospholipase C γ1 and protein kinase C pathways

Loss of ADAM17-Mediated Tumor Necrosis Factor Alpha Signaling in Intestinal Cells Attenuates Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

Chemopreventive effect of a novel, selective TACE inhibitor on DMBA- and TPA-induced skin carcinogenesis

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