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Dynamic expression of epidermal caspase 8 simulates a wound healing response.

Lee P, Lee DJ, Chan C, Chen SW, Ch'en I, Jamora C - Nature (2009)

Bottom Line: The non-canonical secretion of IL1alpha is induced by a p38-MAPK-mediated upregulation of NALP3 (also known as NLRP3), leading to inflammasome assembly and caspase 1 activation.Notably, the increased proliferation of basal keratinocytes is counterbalanced by the growth arrest of suprabasal keratinocytes in the stratified epidermis by IL1alpha-dependent NFkappaB signalling.Altogether, our findings illustrate how the loss of caspase 8 can affect more than programmed cell death to alter the local microenvironment and elicit processes common to wound repair and many neoplastic skin disorders.

View Article: PubMed Central - PubMed

Affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, Natural Science Building, Room 6311, 9500 Gilman Drive, MC 0380, La Jolla, California 92093, USA.

ABSTRACT
Tissue homeostasis and regeneration are regulated by an intricate balance of seemingly competing processes-proliferation versus differentiation, and cell death versus survival. Here we demonstrate that the loss of epidermal caspase 8, an important mediator of apoptosis, recapitulates several phases of a wound healing response in the mouse. The epidermal hyperplasia in the caspase 8 skin is the culmination of signals exchanged between epidermal keratinocytes, dermal fibroblasts and leukocytic cells. This reciprocal interaction is initiated by the paracrine signalling of interleukin 1alpha (IL1alpha), which activates both skin stem cell proliferation and cutaneous inflammation. The non-canonical secretion of IL1alpha is induced by a p38-MAPK-mediated upregulation of NALP3 (also known as NLRP3), leading to inflammasome assembly and caspase 1 activation. Notably, the increased proliferation of basal keratinocytes is counterbalanced by the growth arrest of suprabasal keratinocytes in the stratified epidermis by IL1alpha-dependent NFkappaB signalling. Altogether, our findings illustrate how the loss of caspase 8 can affect more than programmed cell death to alter the local microenvironment and elicit processes common to wound repair and many neoplastic skin disorders.

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Effect of caspase-8 downregulation in the epidermisA. In situ hybridization of Caspase-8 RNA on 0, 1, 7 and 14 days after excisional wounds. Arrows denote wound sites. Distal (>5mm) and proximal (<1mm) refer to the distance from the wound site.B. Differentiation in the wild type (WT) and knockout (KO) epidermis. K5, K1, and loricrin stain the basal, spinous, and granular layers respectively. Dotted line denotes the basement membrane.C. Hyperproliferation of the epidermis in the KO skin is revealed by increased expression of Ki67.
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Figure 1: Effect of caspase-8 downregulation in the epidermisA. In situ hybridization of Caspase-8 RNA on 0, 1, 7 and 14 days after excisional wounds. Arrows denote wound sites. Distal (>5mm) and proximal (<1mm) refer to the distance from the wound site.B. Differentiation in the wild type (WT) and knockout (KO) epidermis. K5, K1, and loricrin stain the basal, spinous, and granular layers respectively. Dotted line denotes the basement membrane.C. Hyperproliferation of the epidermis in the KO skin is revealed by increased expression of Ki67.

Mentions: In the course of characterizing proteins that potentially affect epidermal homeostasis, we observed that epidermal caspase-8 normally fluctuates during the course of a wound healing response (Fig. 1a). In situ hybridization revealed that sites proximal (<1mm) to an excisional wound displayed a thickened epidermis coincident with a downregulation of caspase-8 RNA. However at sites distal (∼5mm) to the wound in which epidermal thickness appeared normal, caspase-8 RNA was unchanged. Upon wound closure (day 14) epidermal hyperplasia subsides and caspase-8 RNA expression was restored. The development of all epidermal layers prior to the onset of caspase-8 expression supports the notion that this protein is not involved in epidermal morphogenesis but rather monitors epidermal integrity amidst assaults from the external environment (Supplementary Figure 1b).


Dynamic expression of epidermal caspase 8 simulates a wound healing response.

Lee P, Lee DJ, Chan C, Chen SW, Ch'en I, Jamora C - Nature (2009)

Effect of caspase-8 downregulation in the epidermisA. In situ hybridization of Caspase-8 RNA on 0, 1, 7 and 14 days after excisional wounds. Arrows denote wound sites. Distal (>5mm) and proximal (<1mm) refer to the distance from the wound site.B. Differentiation in the wild type (WT) and knockout (KO) epidermis. K5, K1, and loricrin stain the basal, spinous, and granular layers respectively. Dotted line denotes the basement membrane.C. Hyperproliferation of the epidermis in the KO skin is revealed by increased expression of Ki67.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2666261&req=5

Figure 1: Effect of caspase-8 downregulation in the epidermisA. In situ hybridization of Caspase-8 RNA on 0, 1, 7 and 14 days after excisional wounds. Arrows denote wound sites. Distal (>5mm) and proximal (<1mm) refer to the distance from the wound site.B. Differentiation in the wild type (WT) and knockout (KO) epidermis. K5, K1, and loricrin stain the basal, spinous, and granular layers respectively. Dotted line denotes the basement membrane.C. Hyperproliferation of the epidermis in the KO skin is revealed by increased expression of Ki67.
Mentions: In the course of characterizing proteins that potentially affect epidermal homeostasis, we observed that epidermal caspase-8 normally fluctuates during the course of a wound healing response (Fig. 1a). In situ hybridization revealed that sites proximal (<1mm) to an excisional wound displayed a thickened epidermis coincident with a downregulation of caspase-8 RNA. However at sites distal (∼5mm) to the wound in which epidermal thickness appeared normal, caspase-8 RNA was unchanged. Upon wound closure (day 14) epidermal hyperplasia subsides and caspase-8 RNA expression was restored. The development of all epidermal layers prior to the onset of caspase-8 expression supports the notion that this protein is not involved in epidermal morphogenesis but rather monitors epidermal integrity amidst assaults from the external environment (Supplementary Figure 1b).

Bottom Line: The non-canonical secretion of IL1alpha is induced by a p38-MAPK-mediated upregulation of NALP3 (also known as NLRP3), leading to inflammasome assembly and caspase 1 activation.Notably, the increased proliferation of basal keratinocytes is counterbalanced by the growth arrest of suprabasal keratinocytes in the stratified epidermis by IL1alpha-dependent NFkappaB signalling.Altogether, our findings illustrate how the loss of caspase 8 can affect more than programmed cell death to alter the local microenvironment and elicit processes common to wound repair and many neoplastic skin disorders.

View Article: PubMed Central - PubMed

Affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, Natural Science Building, Room 6311, 9500 Gilman Drive, MC 0380, La Jolla, California 92093, USA.

ABSTRACT
Tissue homeostasis and regeneration are regulated by an intricate balance of seemingly competing processes-proliferation versus differentiation, and cell death versus survival. Here we demonstrate that the loss of epidermal caspase 8, an important mediator of apoptosis, recapitulates several phases of a wound healing response in the mouse. The epidermal hyperplasia in the caspase 8 skin is the culmination of signals exchanged between epidermal keratinocytes, dermal fibroblasts and leukocytic cells. This reciprocal interaction is initiated by the paracrine signalling of interleukin 1alpha (IL1alpha), which activates both skin stem cell proliferation and cutaneous inflammation. The non-canonical secretion of IL1alpha is induced by a p38-MAPK-mediated upregulation of NALP3 (also known as NLRP3), leading to inflammasome assembly and caspase 1 activation. Notably, the increased proliferation of basal keratinocytes is counterbalanced by the growth arrest of suprabasal keratinocytes in the stratified epidermis by IL1alpha-dependent NFkappaB signalling. Altogether, our findings illustrate how the loss of caspase 8 can affect more than programmed cell death to alter the local microenvironment and elicit processes common to wound repair and many neoplastic skin disorders.

Show MeSH
Related in: MedlinePlus