Dynamic expression of epidermal caspase 8 simulates a wound healing response
Open accessAbstract
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 null 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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Keratinocytes produce large amounts of IL-1α and less IL-1β, whereas epidermal DCs, called Langerhans cells, as well as wound-infiltrating macrophages produce mostly IL-1β, but not IL-1α.
“Keratinocytes produce large amounts of IL-1α and less IL-1β,30,52 whereas epidermal DCs, called Langerhans cells, as well as wound-infiltrating macrophages produce mostly IL-1β, but not IL-1α.”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [52]
An elegant study by Lee et al. demonstrated that IL-1α is negatively regulated by caspase-8.
“An elegant study by Lee et al. demonstrated that IL-1α is negatively regulated by caspase-8.52”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [52]
Skin injury, induced either by UV radiation, skin irritants, or trauma, has been shown to liberate ATP into the extracellular space, which acts as a trigger for NALP3 inflammasome activation and subsequent IL-1β secretion.
“Furthermore, skin injury, induced either by UV radiation, skin irritants, or trauma, has been shown to liberate ATP into the extracellular space, which acts as a trigger for NALP3 inflammasome activation and subsequent IL-1β secretion.30,52,54”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [52]
Caspase-8 becomes downregulated upon wounding in the granular epidermal layer, and IL-1α subsequently mediates keratinocyte proliferation in a paracrine manner by first stimulating fibroblasts of the underlying dermis to secrete cytokines, which then induce keratinocyte division.
“Caspase-8 becomes downregulated upon wounding in the granular epidermal layer, and IL-1α subsequently mediates keratinocyte proliferation in a paracrine manner by first stimulating fibroblasts of the underlying dermis to secrete cytokines, which then induce keratinocyte division.”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [52]
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Cites
Inflammatory cells during wound repair: the good, the bad and the ugly
Martin, P., & Leibovich, S. J. (2005) · Trends in Cell Biology · doi:10.1016/j.tcb.2005.09.002 · Cited by 1,340 · see citing works
Ito, M., Liu, Y., Yang, Z., Nguyen, J., Liang, F., Morris, R. J., & Cotsarelis, G. (2005) · Nature Medicine · doi:10.1038/nm1328 · Cited by 1,317 · see citing works
Chun, H. J., Zheng, L., Ahmad, M., Wang, J., Speirs, C. K., Siegel, R. M., Dale, J. K., Puck, J. M., Davis, J., Hall, C. G., et al. (2002) · Nature · doi:10.1038/nature01063 · Cited by 706 · see citing works
Vasioukhin, V., Degenstein, L., Wise, B., & Fuchs, E. (1999) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.96.15.8551 · Cited by 691 · see citing works
Epithelial Stem Cells: A Folliculocentric View
Cotsarelis, G. (2006) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700376 · Cited by 551 · see citing works
The Inflammasome Mediates UVB-Induced Activation and Secretion of Interleukin-1β by Keratinocytes
Feldmeyer, L., Keller, M., Niklaus, G., Hohl, D., Werner, S., & Beer, H.-D. (2007) · Current Biology · doi:10.1016/j.cub.2007.05.074 · Cited by 544 · see citing works
Stem cells of the skin epithelium
Alonso, L. C., & Fuchs, E. V. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1734203100 · Cited by 521 · see citing works
Distinct Stem Cell Populations Regenerate the Follicle and Interfollicular Epidermis
Levy, V., Lindon, C., Harfe, B. D., & Morgan, B. A. (2005) · Developmental Cell · doi:10.1016/j.devcel.2005.11.003 · Cited by 419 · see citing works
Hohl, D., Mehrel, T., Lichti, U. F., Turner, M. L. C., Roop, D. R., & Steinert, P. M. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)38163-8 · Cited by 309 · see citing works
p120-Catenin Mediates Inflammatory Responses in the Skin
Pérez‐Moreno, M., Davis, M. A., Wong, E., Pasolli, H. A., Reynolds, A. B., & Fuchs, E. V. (2006) · Cell · doi:10.1016/j.cell.2005.11.043 · Cited by 264 · see citing works
Aravalli, R. N., Hu, S., Rowen, T. N., Palmquist, J. M., & Lokensgard, J. R. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.7.4189 · Cited by 251 · see citing works
Keratinocyte apoptosis in epidermal development and disease.
Raj, D., Brash, D., & Grossman, D. (2006) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700008 · Cited by 236 · see citing works
Interleukin-1 and cutaneous inflammation: a crucial link between innate and acquired immunity.
Murphy, J., Robert, C., & Kupper, T. (2000) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.2000.00917.x · Cited by 214 · see citing works
Interleukin 1 is present in normal human epidermis.
Hauser, C. J., Saurat, J. ‐., Schmitt, A., Jaunin, F., & Dayer, J. (1986) · The Journal of Immunology · doi:10.4049/jimmunol.136.9.3317 · Cited by 213 · see citing works
JNK signaling pathway required for wound healing in regenerating Drosophila wing imaginal discs
Bosch, M., Serras, F., Martı́n-Blanco, E., & Baguñà, J. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.01.002 · Cited by 197 · see citing works
Groves, R. W., Mizutani, H., Kieffer, J. D., & Kupper, T. S. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.25.11874 · Cited by 193 · see citing works
Skin γδ T‐cell functions in homeostasis and wound healing
Jameson, J., & Havran, W. L. (2007) · Immunological Reviews · doi:10.1111/j.1600-065x.2006.00483.x · Cited by 184 · see citing works
Paracrine regulation of keratinocyte proliferation and differentiation
Werner, S., & Smola, H. (2001) · Trends in Cell Biology · doi:10.1016/s0962-8924(01)01955-9 · Cited by 183 · see citing works
Cutting Edge: Innate Immunity Conferred by B Cells Is Regulated by Caspase-8
Beisner, D. R., Ch’en, I. L., Kolla, R. V., Hoffmann, A., & Hedrick, S. Μ. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.6.3469 · Cited by 181 · see citing works
Self-citationYamanaka, K., Tanaka, M., Tsutsui, H., Kupper, T. S., Asahi, K., Okamura, H., Nakanishi, K., Suzuki, M., Kayagaki, N., Black, R. A., et al. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.2.997 · Cited by 135 · see citing works
Links between α-catenin, NF-κB, and squamous cell carcinoma in skin
Kobielak, A., & Fuchs, E. V. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510422103 · Cited by 124 · see citing works
Kaufman, C. K., & Fuchs, E. V. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.149.5.999 · Cited by 118 · see citing works
The Activity of Caspase-1 Is Increased in Lesional Psoriatic Epidermis
Johansen, C., Moeller, K., Kragballe, K., & Iversen, L. (2007) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700922 · Cited by 101 · see citing works
Almashat, H., Kandru, S., Liu, R., Behl, Y., Desta, T., & Graves, D. T. (2006) · Diabetes · doi:10.2337/diabetes.55.02.06.db05-1201 · Cited by 93 · see citing works
Hobbs, R. M., Silva-Vargas, V., Groves, R. W., & Watt, F. M. (2004) · Journal of Investigative Dermatology · doi:10.1111/j.0022-202x.2004.23225.x · Cited by 92 · see citing works
Sunburned skin activates inflammasomes
Faustin, B., & Reed, J. C. (2007) · Trends in Cell Biology · doi:10.1016/j.tcb.2007.10.004 · Cited by 90 · see citing works
Li, J., Yin, H. L., & Yuan, J. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200711082 · Cited by 75 · see citing works
Murphy, J.-E., Morales, R. E., Scott, J. E., & Kupper, T. S. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.11.5697 · Cited by 71 · see citing works
Structural, expression, and evolutionary analysis of mouse CIAS1
Anderson, J. P., Mueller, J. L., Rosengren, S., Boyle, D. L., Schaner, P. E., Cannon, S. B., Goodyear, C. S., & Hoffman, H. M. (2004) · Gene · doi:10.1016/j.gene.2004.05.002 · Cited by 55 · see citing works
Hobbs, R. M., & Watt, F. M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300513200 · Cited by 47 · see citing works
Lack of phospholipase C-δ1 induces skin inflammation
Ichinohe, M., Nakamura, Y., Sai, K., Nakahara, M., Yamaguchi, H., & Fukami, K. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.03.082 · Cited by 45 · see citing works
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RIP3 mediates the embryonic lethality of caspase-8-deficient mice
Kaiser, W. J., Upton, J. W., Long, A. B., Livingston-Rosanoff, D., Daley-Bauer, L. P., Hakem, R., Caspary, T., & Mocarski, E. S. (2011) · Nature · doi:10.1038/nature09857 · Cited by 1,057 · see citing works
Eckhart, L., Lippens, S., Tschachler, E., & Declercq, W. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.06.010 · Cited by 515 · see citing works
Caspases Connect Cell-Death Signaling to Organismal Homeostasis
Galluzzi, L., López-Soto, A., Kumar, S., & Kroemer, G. (2016) · Immunity · doi:10.1016/j.immuni.2016.01.020 · Cited by 350 · see citing works
Survival Function of the FADD-CASPASE-8-cFLIPL Complex
Dillon, C. P., Oberst, A., Weinlich, R., Janke, L. J., Kang, T.-B., Ben-Moshe, T., Mak, T. W., Wallach, D., & Green, D. R. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.03.010 · Cited by 331 · see citing works
“, 2004), skin (Keratin 5 or 14-Cre) (Kovalenko et al., 2009; Lee et al., 2009), or intestinal epithelium (Villin-Cre) (Gunther et al.”
BackgroundBonnet, M. C., Preukschat, D., Welz, P.-S., van Loo, G., Ermolaeva, M. A., Bloch, W., Haase, I., & Pasparakis, M. (2011) · Immunity · doi:10.1016/j.immuni.2011.08.014 · Cited by 295 · see citing works
The Innate Immune System in Acute and Chronic Wounds
MacLeod, A. S., & Mansbridge, J. N. (2016) · Advances in Wound Care · doi:10.1089/wound.2014.0608 · Cited by 289 · see citing works
“demonstrated that IL-1a is negatively regulated by caspase-8.(52) Caspase-8 becomes downregulated upon wounding in the granular epidermal layer, and IL-1a subsequently mediates keratinocyte proliferation in a paracrine manner by first stimulating fibroblasts of the underlying dermis to secrete cytokines, which then in…”
BackgroundProtective Roles for Caspase-8 and cFLIP in Adult Homeostasis
Weinlich, R., Oberst, A., Dillon, C. P., Janke, L. J., Milasta, S., Lukens, J. R., Rodriguez, D. A., Gurung, P., Savage, C., Kanneganti, T. D., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.08.045 · Cited by 157 · see citing works
Surviving apoptosis: life–death signaling in single cells
Flusberg, D. A., & Sorger, P. K. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.03.003 · Cited by 149 · see citing works
Temporal Smad7 Transgene Induction in Mouse Epidermis Accelerates Skin Wound Healing
Han, G., Li, F., ten Dijke, P., & Wang, X.-J. (2011) · The American Journal of Pathology · doi:10.1016/j.ajpath.2011.06.003 · Cited by 39 · see citing works
- Authors
- Lee, P., Lee, D.-J., Chan, C., Chen, S.-W., Ch’en, I., & Jamora, C.
- Corresponding author
- Jamora, Colin
- ORCID
- Jamora, Colin
- Venue
- Nature
- Published
- 2009-02-08
- Volume
- 458
- Issue
- 7237
- Pages
- 519-523
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2666261
- OpenAlex
- W1997080155
- Cited by
- 163
- References
- 31
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 8 · 2022: 2 · 2021: 10 · 2020: 7 · 2019: 17 · 2018: 4 · 2017: 9 · 2016: 10 · 2015: 13 · 2014: 11 · 2013: 16 · 2012: 10
- FWCI
- 14.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Dermatology Foundation
- National Institutes of Health
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR053185)
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- caspase-8, wound healing, skin homeostasis, keratinocytes, epidermal hyperplasia, interleukin-1 alpha, inflammasome, NLRP3, p38 MAPK, caspase-1, NF-κB signaling, keratinocyte proliferation, skin inflammation, skin stem cells
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Epidermal Cells, Animals, Carrier Proteins, Cornea, Epidermis, Inflammation, Mesoderm, Wound Healing, Down-Regulation, Keratinocytes, NF-kappa B, Mice, Knockout, Paracrine Communication, Caspase 1, Mice, Caspase 8, Interleukin-1alpha, Alstrom Syndrome
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