The caspase-1 inhibitor CARD18 is specifically expressed during late differentiation of keratinocytes and its expression is lost in lichen planus

Qin, Haihong; Jin, Jun‐O; Fischer, H.; Mildner, Michael; Gschwandtner, Maria; Mlitz, Veronika; Eckhart, Leopold; Tschachler, Erwin

doi:10.1016/j.jdermsci.2017.04.015

Cited by 8 publications

(13 citation statements)

References 33 publications

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“…The crystal structure of GSDMA3 was determined, serving as a model for other gasdermins including the pyroptotic pore-forming GSDMD protein 19 . Recently, we showed that the caspase-1 inhibitor CARD18, also known as ICEBERG 20 is predominantly expressed during terminal differentiation of epidermal keratinocytes 21 .…”

Section: Introductionmentioning

confidence: 99%

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

Lachner

Mlitz

Tschachler

et al. 2017

Sci Rep

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120

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The homeostasis of the epidermis depends on keratinocyte differentiation and cornification, a mode of programmed cell death that does not elicit inflammation. Here, we report that cornification is associated with the expression of specific genes that control multiple steps of pyroptosis, another form of cell death that involves the processing and release of interleukin-1 family (IL1F) cytokines. Expression levels of pro-inflammatory IL1A and IL1B and of the pyroptotic pore-forming gasdermin (GSDM) D were downregulated during terminal differentiation of human keratinocytes in vitro. By contrast, negative regulators of IL-1 processing, including NLR family pyrin domain containing 10 (NLRP10) and pyrin domain-containing 1 (PYDC1), the anti-inflammatory IL1F members IL-37 (IL1F7) and IL-38 (IL1F10), and GSDMA, were strongly induced in differentiated keratinocytes. In human tissues, these keratinocyte differentiation-associated genes are expressed in the skin at higher levels than in any other organ, and mammalian species, that have lost the epidermal cornification program during evolution, i.e. whales and dolphins, lack homologs of these genes. Together, our results suggest that human epidermal cornification is accompanied by a tight control of pyroptosis and warrant further studies of potential defects in the balance between cornification and pyroptosis in skin pathologies.

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Section: Introductionmentioning

confidence: 99%

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

Lachner

Mlitz

Tschachler

et al. 2017

Sci Rep

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120

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“…These proteins (CARD18, PYDC1, NLRP10) have domains that facilitate homotypic interaction with other pyroptosis proteins while their lack of effector domains suppresses the assembly of inflammasomes (Figure ). Caspase recruitment domain family member 18 (CARD18), previously identified as an inhibitor of caspase‐1 is predominantly expressed in epidermal keratinocytes during normal terminal differentiation and decreased in the skin of patients with lichen planus . Knockdown of CARD18 in keratinocytes did not impair cornification in skin models but resulted in higher levels of IL‐1b .…”

Section: Epidermal Keratinocytes Suppress Inflammation During Normal mentioning

confidence: 98%

“…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%

“…Caspase recruitment domain family member 18 (CARD18), previously identified as an inhibitor of caspase‐1 is predominantly expressed in epidermal keratinocytes during normal terminal differentiation and decreased in the skin of patients with lichen planus . 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 .…”

Section: Epidermal Keratinocytes Suppress Inflammation During Normal mentioning

confidence: 99%

“…A major challenge in this context is differences between the skin of humans and model organisms with regard to the regulation of pyroptosis. For instance, the mouse lacks CARD18 and has three homologs of GSDMA . Human in vitro skin models have other shortcomings, such as the absence of resident immune cells which likely serve as amplifiers of inflammation in vivo .…”

Section: The Concept Of Cornification As Potentially Dangerous Cell Dmentioning

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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The Psoriatic Nonlesional Skin: A Battlefield between Susceptibility and Protective Factors

Kelemen

Bozó

Groma

et al. 2021

Journal of Investigative Dermatology

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The caspase-1 inhibitor CARD18 is specifically expressed during late differentiation of keratinocytes and its expression is lost in lichen planus

Cited by 8 publications

References 33 publications

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

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

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

The Psoriatic Nonlesional Skin: A Battlefield between Susceptibility and Protective Factors

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