Epidermal cornification is preceded by the expression of a keratinocyte-specific set of pyroptosis-related genes

Lachner, Julia; Mlitz, Veronika; Tschachler, Erwin; Eckhart, Leopold

doi:10.1038/s41598-017-17782-4

Cited by 79 publications

(133 citation statements)

References 62 publications

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“…There is evidence that GSDMD forms also pores in organelles, leading to the decay of mitochondria and lysosomes prior to the rupture of the plasma membrane . Many components of the pyroptotic molecular machinery are expressed and can be activated in epidermal keratinocytes . A homolog of GSDMD, GSDMA, is expressed specifically in keratinocytes and it will be important to determine whether GSDMA contributes to the subcellular changes during differentiated‐associated cell death of keratinocytes in the epidermis and skin appendages.…”

Section: Cell Death Is a Major Trigger Of Inflammation Unless Alarm Smentioning

confidence: 99%

“…Structurally similar IL‐1 family members of the opposite biological effect, that is suppression of inflammation, are IL‐1 receptor antagonist (RN), IL‐36RN, IL‐37 and IL‐38 . IL‐1 family cytokines are differentially expressed in epidermal keratinocytes, and, remarkably, IL‐36β, IL‐36γ, IL‐36RN, IL‐37 and IL‐38 are expressed in keratinocytes at higher levels than in any other cell type …”

Section: Cell Death Is a Major Trigger Of Inflammation Unless Alarm Smentioning

confidence: 99%

“…Cornification genes encode proteinaceous components of the cornified envelope (eg loricrin), transglutaminases, mediators of the synthesis and transport of skin barrier lipids (eg ABCA12) mediators of degradation processes (eg DNase1L2) and regulators of enzyme activities (eg SPINK5) Other keratinocyte differentiation‐associated proteins do not contribute to cornification itself but appear to suppress processes different from cornification. In particular, potentially anti‐inflammatory proteins were found in general gene expression screenings of differentiating keratinocytesand more recently in studies focused on the expression of gene families related to pyroptosis in keratinocytes . The putative suppressors of pro‐inflammatory signals in cornification include (i) modulators of pyroptosis, (ii) antagonists of IL‐1 family cytokines and (iii) inhibitors of non‐homeostatic cell processes.…”

Section: Epidermal Keratinocytes Suppress Inflammation During Normal mentioning

confidence: 99%

“…Knockdown of CARD18 in keratinocytes did not impair cornification in skin models but resulted in higher levels of IL‐1b . Pyrin domain containing 1 (PYDC1), an inhibitor of inflammasomes and pro‐inflammatory signalling is massively upregulated during keratinocyte differentiation at least at the mRNA level . NOD‐like receptor family pyrin domain containing 10 (NLRP10), which lacks the leucine‐rich domain present in pro‐inflammatory NLRPs, inhibits inflammation and is predominantly expressed in terminally differentiated keratinocytes (Figure , right panel; Figure ) .…”

Section: Epidermal Keratinocytes Suppress Inflammation During Normal mentioning

confidence: 99%

“…Pyrin domain containing 1 (PYDC1), an inhibitor of inflammasomes and pro‐inflammatory signalling is massively upregulated during keratinocyte differentiation at least at the mRNA level . NOD‐like receptor family pyrin domain containing 10 (NLRP10), which lacks the leucine‐rich domain present in pro‐inflammatory NLRPs, inhibits inflammation and is predominantly expressed in terminally differentiated keratinocytes (Figure , right panel; Figure ) . Knockout of NLRP10 did not impair epidermal cornification but reduced contact hypersensitivity responses in mice .…”

Section: Epidermal Keratinocytes Suppress Inflammation During Normal mentioning

confidence: 99%

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Control of cell death‐associated danger signals during cornification prevents autoinflammation of the skin

Eckhart

Tschachler

2018

Experimental Dermatology

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The function of the skin as a barrier to the environment is mainly achieved by the outermost layers of the epidermis. In the granular layer, epidermal keratinocytes undergo the last steps of their terminal differentiation program resulting in cornification. The coordinated conversion of living keratinocytes into corneocytes, the building blocks of the cornified layer, represents a unique form of programmed cell death. Recent studies have identified numerous genes that are specifically expressed in terminally differentiated keratinocytes and, surprisingly, this genetic program does not only include mediators of cornification but also suppressors of pyroptosis, another mode of programmed cell death. Pyroptosis is activated by inflammasomes, leads to the release of interleukin-1 (IL-1) family cytokines, and thereby activates inflammation. In addition, inhibitors of potentially pro-inflammatory proteases and enzymes removing danger-associated cytoplasmic DNA are expressed in differentiated keratinocytes. We propose the concept of cornification as an inherently hazardous process in which damaging side effects are actively suppressed by protective mechanisms. In support of this hypothesis, loss-of-function mutations in epidermal protease inhibitors and IL-1 family antagonists suffice to induce autoinflammation. Similarly, exogenous disturbances of either cornification or its accompanying control mechanisms may be starting points for skin inflammation. Further studies into the relationship between cornification, pyroptosis and other forms of cell death will help to define the initiation phase of inflammatory skin diseases and offer new targets for disease prevention and therapy.

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Section: Cell Death Is a Major Trigger Of Inflammation Unless Alarm Smentioning

confidence: 99%

Section: Cell Death Is a Major Trigger Of Inflammation Unless Alarm Smentioning

confidence: 99%

Section: Epidermal Keratinocytes Suppress Inflammation During Normal mentioning

confidence: 99%

Section: Epidermal Keratinocytes Suppress Inflammation During Normal mentioning

confidence: 99%

Section: Epidermal Keratinocytes Suppress Inflammation During Normal mentioning

confidence: 99%

See 3 more Smart Citations

Control of cell death‐associated danger signals during cornification prevents autoinflammation of the skin

Eckhart

Tschachler

2018

Experimental Dermatology

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Inflammasomes in epithelial innate immunity: front line warriors

Robinson,

Boucher

2024

FEBS Letters

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Our epithelium represents a battle ground against a variety of insults including pathogens and danger signals. It encodes multiple sensors that detect and respond to such insults, playing an essential role in maintaining and defending tissue homeostasis. One key set of defense mechanisms is our inflammasomes which drive innate immune responses including, sensing and responding to pathogen attack, through the secretion of pro‐inflammatory cytokines and cell death. Identification of physiologically relevant triggers for inflammasomes has greatly influenced our ability to decipher the mechanisms behind inflammasome activation. Furthermore, identification of patient mutations within inflammasome components implicates their involvement in a range of epithelial diseases. This review will focus on exploring the roles of inflammasomes in epithelial immunity and cover: the diversity and differential expression of inflammasome sensors amongst our epithelial barriers, their ability to sense local infection and damage and the contribution of the inflammasomes to epithelial homeostasis and disease.

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