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1.
Eur Respir J ; 63(3)2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38097207

RESUMO

BACKGROUND: Neutrophils are important in the pathophysiology of coronavirus disease 2019 (COVID-19), but the molecular changes contributing to altered neutrophil phenotypes following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are not fully understood. We used quantitative mass spectrometry-based proteomics to explore neutrophil phenotypes immediately following acute SARS-CoV-2 infection and during recovery. METHODS: Prospective observational study of hospitalised patients with PCR-confirmed SARS-CoV-2 infection (May to December 2020). Patients were enrolled within 96 h of admission, with longitudinal sampling up to 29 days. Control groups comprised non-COVID-19 acute lower respiratory tract infection (LRTI) and age-matched noninfected controls. Neutrophils were isolated from peripheral blood and analysed using mass spectrometry. COVID-19 severity and recovery were defined using the World Health Organization ordinal scale. RESULTS: Neutrophil proteomes from 84 COVID-19 patients were compared to those from 91 LRTI and 42 control participants. 5800 neutrophil proteins were identified, with >1700 proteins significantly changed in neutrophils from COVID-19 patients compared to noninfected controls. Neutrophils from COVID-19 patients initially all demonstrated a strong interferon signature, but this signature rapidly declined in patients with severe disease. Severe disease was associated with increased abundance of proteins involved in metabolism, immunosuppression and pattern recognition, while delayed recovery from COVID-19 was associated with decreased granule components and reduced abundance of metabolic proteins, chemokine and leukotriene receptors, integrins and inhibitory receptors. CONCLUSIONS: SARS-CoV-2 infection results in the sustained presence of circulating neutrophils with distinct proteomes suggesting altered metabolic and immunosuppressive profiles and altered capacities to respond to migratory signals and cues from other immune cells, pathogens or cytokines.


Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Neutrófilos , Proteoma , Citocinas
2.
J Immunol ; 188(4): 1992-2000, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22246630

RESUMO

IL-1ß and IL-18 are crucial regulators of inflammation and immunity. Both cytokines are initially expressed as inactive precursors, which require processing by the protease caspase-1 for biological activity. Caspase-1 itself is activated in different innate immune complexes called inflammasomes. In addition, caspase-1 activity regulates unconventional protein secretion of many other proteins involved in inflammation and repair. Human caspase-4 is a poorly characterized member of the caspase family, which is supposed to be involved in endoplasmic reticulum stress-induced apoptosis. However, its gene is located on the same locus as the caspase-1 gene, which raises the possibility that caspase-4 plays a role in inflammation. In this study, we show that caspase-4 expression is required for UVB-induced activation of proIL-1ß and for unconventional protein secretion by skin-derived keratinocytes. These processes require expression of the nucleotide-binding domain leucine-rich repeat containing, Pyrin domain containing-3 inflammasome, and caspase-4 physically interacts with its central molecule caspase-1. As the active site of caspase-4 is required for activation of caspase-1, the latter most likely represents a substrate of caspase-4. Caspase-4 expression is also essential for efficient nucleotide-binding domain leucine-rich repeat containing, Pyrin domain containing-3 and for absent in melanoma 2 inflammasome-dependent proIL-1ß activation in macrophages. These results demonstrate an important role of caspase-4 in inflammation and innate immunity through activation of caspase-1. Therefore, caspase-4 represents a novel target for the treatment of (auto)inflammatory diseases.


Assuntos
Caspase 1/biossíntese , Caspases Iniciadoras/imunologia , Caspases Iniciadoras/metabolismo , Inflamassomos/imunologia , Inflamassomos/metabolismo , Proteínas de Transporte/metabolismo , Caspase 1/genética , Caspase 1/imunologia , Caspase 1/metabolismo , Caspases Iniciadoras/genética , Células Cultivadas , Proteínas do Citoesqueleto/metabolismo , Humanos , Interleucina-18/biossíntese , Interleucina-18/imunologia , Interleucina-18/metabolismo , Interleucina-1beta/biossíntese , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Queratinócitos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Pirina , Interferência de RNA , RNA Interferente Pequeno , Raios Ultravioleta
3.
Sci Rep ; 14(1): 5966, 2024 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-38472281

RESUMO

Neutrophils are one of the first responders to infection and are a key component of the innate immune system through their ability to phagocytose and kill invading pathogens, secrete antimicrobial molecules and produce extracellular traps. Neutrophils are produced in the bone marrow, circulate within the blood and upon immune challenge migrate to the site of infection. We wanted to understand whether this transition shapes the mouse neutrophil protein landscape, how the mouse neutrophil proteome is impacted by systemic infection and perform a comparative analysis of human and mouse neutrophils. Using quantitative mass spectrometry we reveal tissue-specific, infection-induced and species-specific neutrophil protein signatures. We show a high degree of proteomic conservation between mouse bone marrow, blood and peritoneal neutrophils, but also identify key differences in the molecules that these cells express for sensing and responding to their environment. Systemic infection triggers a change in the bone marrow neutrophil population with considerable impact on the core machinery for protein synthesis and DNA replication along with environmental sensors. We also reveal profound differences in mouse and human blood neutrophils, particularly their granule contents. Our proteomics data provides a valuable resource for understanding neutrophil function and phenotypes across species and model systems.


Assuntos
Armadilhas Extracelulares , Neutrófilos , Humanos , Animais , Camundongos , Neutrófilos/metabolismo , Proteômica/métodos , Armadilhas Extracelulares/metabolismo , Medula Óssea , Fagocitose
4.
J Biol Chem ; 287(39): 33001-13, 2012 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-22851183

RESUMO

Nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a master regulator of cellular antioxidant defense systems, and activation of this transcription factor is a promising strategy for protection of skin and other organs from environmental insults. To identify efficient Nrf2 activators in keratinocytes, we combined a chemical library screen with computer-based virtual screening. Among 14 novel Nrf2 activators, the most potent compound, a nitrophenyl derivative of 2-chloro-5-nitro-N-phenyl-benzamide, was characterized with regard to its molecular mechanism of action. This compound induced the expression of cytoprotective genes in keratinocytes isolated from wild-type but not from Nrf2-deficient mice. Most importantly, it showed low toxicity and protected primary human keratinocytes from UVB-induced cell death. Therefore, it represents a potential lead compound for the development of drugs for skin protection under stress conditions. Our study demonstrates that chemical library screening combined with advanced computational similarity searching is a powerful strategy for identification of bioactive compounds, and it points toward an innovative therapeutic approach against UVB-induced skin damage.


Assuntos
Benzamidas/farmacologia , Citoproteção/efeitos dos fármacos , Queratinócitos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Raios Ultravioleta/efeitos adversos , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Morte Celular/efeitos da radiação , Linhagem Celular Transformada , Citoproteção/genética , Citoproteção/efeitos da radiação , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/efeitos da radiação , Humanos , Queratinócitos/patologia , Camundongos , Fator 2 Relacionado a NF-E2/genética , Pele/lesões , Pele/metabolismo , Pele/patologia
5.
J Mol Biol ; 434(4): 167335, 2022 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-34757055

RESUMO

All cells must die at some point, and the dogma is that they do it either silently via apoptosis or via pro-inflammatory, lytic forms of death. Amongst these lytic cell death pathways, pyroptosis is one of the best characterized. Pyroptosis depends on inflammatory caspases which activate members of the gasdermin family of proteins, and it is associated with the release of the pro-inflammatory cytokines interleukin (IL)-1ß and IL-18. Pyroptosis is an essential component of innate immunity, it initiates and amplifies inflammation and it removes the replication niche for intracellular pathogens. Most of the literature on pyroptosis focuses on monocytes and macrophages. However, the most abundant phagocytes in humans are neutrophils. This review addresses whether neutrophils undergo pyroptosis and the underlying mechanisms. Furthermore, I discuss how and why neutrophils might be able to resist pyroptosis.


Assuntos
Neutrófilos , Piroptose , Caspases/metabolismo , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Neutrófilos/citologia , Neutrófilos/fisiologia
6.
J Immunol ; 183(9): 5593-9, 2009 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-19843943

RESUMO

Thalidomide is an efficient anti-inflammatory and anti-angiogenic drug, but its therapeutic use is problematic due to a strong teratogenic activity. Nevertheless, thalidomide was approved for the treatment of inflammatory skin diseases and certain types of cancer, and it is extensively tested for several other indications. Recently, we demonstrated that active caspase-1, whose activation is dependent on inflammasome complexes, is required for unconventional protein secretion of proinflammatory cytokines such as IL-1 and of the proangiogenic fibroblast growth factor 2. In this study, we show that pharmacological doses of thalidomide strongly reduced the secretion of both proteins. Thalidomide-treated cells also released less of other leaderless proteins, which require caspase-1 activity for their secretion. In line with these findings, the drug inhibited activation and activity of caspase-1 in cultured cells but not in vitro. The latter finding suggests that the pharmacological activity is exerted by a metabolite of the drug. The anti-inflammatory activity of thalidomide was also mediated via caspase-1 in mice. These findings represent a novel mechanism by which thalidomide exerts its pharmacological activity and suggest that inhibition of the activity of IL-1 might represent a novel strategy to substitute thalidomide.


Assuntos
Caspase 1/metabolismo , Inibidores de Caspase , Talidomida/farmacologia , Inibidores da Angiogênese/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Células COS , Caspase 1/deficiência , Caspase 1/genética , Células Cultivadas , Chlorocebus aethiops , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Ativação Enzimática/imunologia , Fator 2 de Crescimento de Fibroblastos/antagonistas & inibidores , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
7.
FEBS J ; 288(11): 3334-3350, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33047496

RESUMO

Cell death is an integral part of both infectious and sterile inflammatory reactions. Many cell death pathways cause the dying cell to lyse, thereby amplifying inflammation. A special form of lytic cell death is the formation of neutrophil extracellular traps (NETs), large structures of chromatin and antimicrobial proteins, which are released by dying neutrophils to capture extracellular pathogens and limit the spread of infections. The molecular mechanisms of NET formation remain incompletely understood. Recent research demonstrated substantial crosstalk between different cell death pathways, most notably between apoptosis, pyroptosis and necroptosis. Here, we review suicidal and vital NET formation and discuss potential crosstalk of their mechanisms of release with other forms of cell death.


Assuntos
Cromatina/genética , Armadilhas Extracelulares/genética , Inflamação/genética , Micoses/genética , Apoptose/genética , Morte Celular/genética , Armadilhas Extracelulares/microbiologia , Humanos , Inflamação/sangue , Inflamação/microbiologia , Micoses/sangue , Micoses/microbiologia , Neutrófilos/microbiologia , Transdução de Sinais/genética
8.
Elife ; 92020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32391789

RESUMO

Neutrophils are important innate immune cells that tackle invading pathogens with different effector mechanisms. They acquire this antimicrobial potential during their maturation in the bone marrow, where they differentiate from hematopoietic stem cells in a process called granulopoiesis. Mature neutrophils are terminally differentiated and short-lived with a high turnover rate. Here, we show a critical role for linker histone H1 on the differentiation and function of neutrophils using a genome-wide CRISPR/Cas9 screen in the human cell line PLB-985. We systematically disrupted expression of somatic H1 subtypes to show that individual H1 subtypes affect PLB-985 maturation in opposite ways. Loss of H1.2 and H1.4 induced an eosinophil-like transcriptional program, thereby negatively regulating the differentiation into the neutrophil lineage. Importantly, H1 subtypes also affect neutrophil differentiation and the eosinophil-directed bias of murine bone marrow stem cells, demonstrating an unexpected subtype-specific role for H1 in granulopoiesis.


Assuntos
Células-Tronco Hematopoéticas/citologia , Histonas/fisiologia , Neutrófilos/citologia , Animais , Medula Óssea/fisiologia , Sistemas CRISPR-Cas , Diferenciação Celular , Linhagem Celular , Eosinófilos/citologia , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Hematopoese , Humanos , Camundongos , Microscopia Eletrônica de Transmissão , Fatores de Transcrição/fisiologia
9.
Dev Cell ; 44(5): 542-553, 2018 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-29533770

RESUMO

Neutrophils are essential to the homeostatic mission of safeguarding host tissues, responding rapidly and diversely to breaches of the host's barriers to infection, and returning tissues to a sterile state. In response to specific stimuli, neutrophils extrude modified chromatin structures decorated with specific cytoplasmic and granular proteins called neutrophil extracellular traps (NETs). Several pathways lead to this unique form of cell death (NETosis). Extracellular chromatin may have evolved to defend eukaryotic organisms against infection, and its release has at least three functions: trapping and killing of microbes, amplifying immune responses, and inducing coagulation. Here we review neutrophil development and heterogeneity with a focus on NETs, NET formation, and their relevance in host defense and disease.


Assuntos
Cromatina/imunologia , Resistência à Doença/imunologia , Armadilhas Extracelulares/imunologia , Imunidade Inata/imunologia , Neutrófilos/imunologia , Animais , Humanos
10.
Sci Immunol ; 3(26)2018 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-30143555

RESUMO

The death of a cell is an inevitable part of its biology. During homeostasis, most cells die through apoptosis. If homeostasis is disturbed, cell death can switch to proinflammatory forms of death, such as necroptosis, pyroptosis, or NETosis. We demonstrate that the formation of neutrophil extracellular traps (NETs), a special form of neutrophil cell death that releases chromatin structures to the extracellular space, is dependent on gasdermin D (GSDMD). GSDMD is a pore-forming protein and an executor of pyroptosis. We screened a chemical library and found a small molecule based on the pyrazolo-oxazepine scaffold that efficiently blocks NET formation and GSDMD-mediated pyroptotic cell death in human cells. During NETosis, GSDMD is proteolytically activated by neutrophil proteases and, in turn, affects protease activation and nuclear expansion in a feed-forward loop. In addition to the central role of GSDMD in pyroptosis, we propose that GSDMD also plays an essential function in NETosis.


Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Morte Celular/fisiologia , Armadilhas Extracelulares/fisiologia , Proteínas de Neoplasias/fisiologia , Neutrófilos/fisiologia , Animais , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos Mutantes , Peptídeo Hidrolases/farmacologia , Proteínas de Ligação a Fosfato
11.
Sci Immunol ; 3(26)2018 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-30143554

RESUMO

Neutrophil extrusion of neutrophil extracellular traps (NETs) and concomitant cell death (NETosis) provides host defense against extracellular pathogens, whereas macrophage death by pyroptosis enables defense against intracellular pathogens. We report the unexpected discovery that gasdermin D (GSDMD) connects these cell death modalities. We show that neutrophil exposure to cytosolic lipopolysaccharide or cytosolic Gram-negative bacteria (Salmonella ΔsifA and Citrobacter rodentium) activates noncanonical (caspase-4/11) inflammasome signaling and triggers GSDMD-dependent neutrophil death. GSDMD-dependent death induces neutrophils to extrude antimicrobial NETs. Caspase-11 and GSDMD are required for neutrophil plasma membrane rupture during the final stage of NET extrusion. Unexpectedly, caspase-11 and GSDMD are also required for early features of NETosis, including nuclear delobulation and DNA expansion; this is mediated by the coordinate actions of caspase-11 and GSDMD in mediating nuclear membrane permeabilization and histone degradation. In vivo application of deoxyribonuclease I to dissolve NETs during murine Salmonella ΔsifA challenge increases bacterial burden in wild-type but not in Casp11-/- and Gsdmd -/- mice. Our studies reveal that neutrophils use an inflammasome- and GSDMD-dependent mechanism to activate NETosis as a defense response against cytosolic bacteria.


Assuntos
Proteínas Reguladoras de Apoptose/imunologia , Caspases/imunologia , Armadilhas Extracelulares/imunologia , Inflamassomos/imunologia , Neutrófilos/imunologia , Animais , Proteínas Reguladoras de Apoptose/genética , Caspases Iniciadoras , Morte Celular , Citrobacter rodentium , Citosol/imunologia , Citosol/microbiologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Lipopolissacarídeos , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Ligação a Fosfato , Infecções por Salmonella/imunologia , Salmonella enterica
12.
PLoS One ; 11(6): e0157454, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27310721

RESUMO

Neutrophils are essential innate immune cells whose responses are crucial in the clearance of invading pathogens. Neutrophils can respond to infection by releasing neutrophil extracellular traps (NETs). NETs are formed of chromatin and specific granular proteins and are released after execution of a poorly characterized cell death pathway. Here, we show that NET formation induced by PMA or Candida albicans is independent of RNA polymerase II and III-mediated transcription as well as of protein synthesis. Thus, neutrophils contain all the factors required for NET formation when they emerge from the bone marrow as differentiated cells.


Assuntos
Armadilhas Extracelulares/imunologia , Regulação da Expressão Gênica/imunologia , Neutrófilos/imunologia , Animais , Candida albicans/imunologia , Quimiocina CCL3/genética , Quimiocina CCL3/imunologia , Cicloeximida/farmacologia , Dactinomicina/farmacologia , Armadilhas Extracelulares/química , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/genética , Flavonoides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-8/genética , Interleucina-8/imunologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/microbiologia , Piperidinas/farmacologia , Cultura Primária de Células , RNA Polimerase II/genética , RNA Polimerase II/imunologia , RNA Polimerase III/genética , RNA Polimerase III/imunologia , Salmonella typhimurium/imunologia , Acetato de Tetradecanoilforbol/farmacologia
13.
J Invest Dermatol ; 135(5): 1395-1404, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25562666

RESUMO

Caspase-1 has a crucial role in innate immunity as the protease activates the proinflammatory cytokine prointerleukin(IL)-1ß. Furthermore, caspase-1 induces pyroptosis, a lytic form of cell death that supports inflammation. Activation of caspase-1 occurs in multi-protein complexes termed inflammasomes, which assemble upon sensing of stress signals. In the skin and in skin-derived keratinocytes, UVB irradiation induces inflammasome-dependent IL-1 secretion and sunburn. Here we present evidence that caspase-1 and caspase-4 are required for UVB-induced apoptosis. In UVB-irradiated human primary keratinocytes, apoptosis occurs significantly later than inflammasome activation but depends on caspase-1 activity. However, it proceeds independently of inflammasome activation. By a proteomics approach, we identified the antiapoptotic Bap31 as a putative caspase-1 substrate. Caspase-1-dependent apoptosis is possibly a recent process in evolution as it was not detected in mice. These results suggest a protective role of caspase-1 in keratinocytes during UVB-induced skin cancer development through the induction of apoptosis.


Assuntos
Apoptose/efeitos da radiação , Caspase 1/metabolismo , Queratinócitos/patologia , Raios Ultravioleta/efeitos adversos , Animais , Caspase 1/efeitos dos fármacos , Caspase 1/genética , Caspases Iniciadoras/metabolismo , Células Cultivadas , Feminino , Humanos , Inflamassomos/metabolismo , Queratinócitos/metabolismo , Queratinócitos/efeitos da radiação , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Modelos Animais , RNA Interferente Pequeno/farmacologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/prevenção & controle
14.
Cell Host Microbe ; 15(5): 526-36, 2014 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-24832448

RESUMO

Neutrophils are endowed with a plethora of toxic molecules that are mobilized in immune responses. These cells evolved to fight infections, but when deployed at the wrong time and in the wrong place, they cause damage to the host. Here, we review the generalities of these cells as well as the difficulties encountered when trying to unravel them mechanistically. We then focus on how neutrophils develop and their function in infection. We center our attention on human neutrophils and what we learn from clinical immunodeficiencies. Finally, we use autoimmune disease to illustrate the harmful potential of dysregulated neutrophil responses.


Assuntos
Doenças Autoimunes/imunologia , Infecções/imunologia , Neutrófilos/imunologia , Animais , Humanos
15.
Innate Immun ; 20(2): 115-25, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23676582

RESUMO

Caspase-1 plays a fundamental role in innate immunity and in several important inflammatory diseases as the protease activates the pro-inflammatory cytokines proIL-1ß and proIL-18. Caspase-1 itself is activated in different inflammasome complexes, which assemble in response to a variety of exogenous and endogenous stressors. More recently, pyroptosis, a caspase-1-dependent type of programmed cell death, has been identified that is able to support secreted IL-1 and IL-18 in triggering an inflammatory response. Whereas these 'canonical' activities are well appreciated, this review also highlights less-known pathways and molecules activated by caspase-1. There is evidence that caspase-1 supports cell survival by activation of NF-κB, induction of membrane repair and regulation of unconventional secretion of certain proteins. The physiologic effects of processing of other downstream targets, such as proteins involved in glycolysis or activation of caspase-7, are less well understood. However, there is increasing evidence that caspase-1 contributes to innate and adaptive immunologic defense mechanisms, repair and pathologic conditions by the regulation of several different and partially opposing pathways.


Assuntos
Caspase 1/imunologia , Inflamassomos/metabolismo , NF-kappa B/metabolismo , Imunidade Adaptativa , Animais , Apoptose/imunologia , Caspase 7/imunologia , Sobrevivência Celular , Glicólise , Humanos , Imunidade Inata , Inflamassomos/imunologia , Mediadores da Inflamação/metabolismo , Interleucina-18/imunologia , Interleucina-18/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Transdução de Sinais
16.
Sci Signal ; 2(78): pe40, 2009 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-19584354

RESUMO

The epidermis is part of the innate immune system and represents the first line of defense against external insults. It must continuously replace differentiated or damaged keratinocytes, and this is maintained through a multilayered structure and a dynamic equilibrium between proliferation of stem cells and transit-amplifying cells in the basal layer and differentiation in suprabasal layers. At the surface of the epidermis, keratinocytes die by a specific and well-orchestrated terminal differentiation process, and the resulting dead corneocytes play an essential function as the first barrier against the environment. New evidence demonstrates that keratinocyte-specific ablation of the apoptotic caspase-8 in mice destroys the balance in the epidermis. Although differentiation in the outermost epidermal layers of these mice is normal, the mice suffer from strong cutaneous inflammation because of enhanced production and secretion of the proinflammatory cytokine pro-interleukin-1alpha.


Assuntos
Caspase 8/metabolismo , Epiderme/enzimologia , Queratinócitos/enzimologia , Animais , Diferenciação Celular , Proliferação de Células , Dermatite/metabolismo , Dermatite/patologia , Epiderme/patologia , Interleucina-1alfa/metabolismo , Queratinócitos/patologia , Camundongos
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