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1.
Immunity ; 35(4): 572-82, 2011 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-22000287

RESUMO

Epidermal keratinocytes provide an essential structural and immunological barrier forming the first line of defense against potentially pathogenic microorganisms. Mechanisms regulating barrier integrity and innate immune responses in the epidermis are important for the maintenance of skin immune homeostasis and the pathogenesis of inflammatory skin diseases. Here, we show that epidermal keratinocyte-restricted deficiency of the adaptor protein FADD (FADD(E-KO)) induced severe inflammatory skin lesions in mice. The development of skin inflammation in FADD(E-KO) mice was triggered by RIP kinase 3 (RIP3)-mediated programmed necrosis (termed necroptosis) of FADD-deficient keratinocytes, which was partly dependent on the deubiquitinating enzyme CYLD and tumor necrosis factor (TNF)-TNF receptor 1 signaling. Collectively, our findings provide an in vivo experimental paradigm that regulation of necroptosis in keratinocytes is important for the maintenance of immune homeostasis and the prevention of chronic inflammation in the skin.


Assuntos
Apoptose , Dermatite/imunologia , Dermatite/patologia , Epiderme/imunologia , Proteína de Domínio de Morte Associada a Fas/imunologia , Queratinócitos/imunologia , Animais , Células Cultivadas , Dermatite/metabolismo , Proteína de Domínio de Morte Associada a Fas/deficiência , Homeostase , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/metabolismo , Necrose , Transdução de Sinais
2.
Cell Microbiol ; 12(7): 939-61, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20109161

RESUMO

The immunity-related GTPases (IRGs) constitute an interferon-induced intracellular resistance mechanism in mice against Toxoplasma gondii. IRG proteins accumulate on the parasitophorous vacuole membrane (PVM), leading to its disruption and to death of the parasite. How IRGs target the PVM is unknown. We show that accumulation of IRGs on the PVM begins minutes after parasite invasion and increases for about 1 h. Targeting occurs independently of several signalling pathways and the microtubule network, suggesting that IRG transport is diffusion-driven. The intensity of IRG accumulation on the PVM, however, is reduced in absence of the autophagy regulator, Atg5. In wild-type cells IRG proteins accumulate cooperatively on PVMs in a definite order reflecting a temporal hierarchy, with Irgb6 and Irgb10 apparently acting as pioneers. Loading of IRG proteins onto the vacuoles of virulent Toxoplasma strains is attenuated and the two pioneer IRGs are the most affected. The polymorphic rhoptry kinases, ROP16, ROP18 and the catalytically inactive proteins, ROP5A-D, are not individually responsible for this effect. Thus IRG proteins protect mice against avirulent strains of Toxoplasma but fail against virulent strains. The complex cooperative behaviour of IRG proteins in resisting Toxoplasma may hint at undiscovered complexity also in virulence mechanisms.


Assuntos
Proteínas de Ligação ao GTP/metabolismo , Toxoplasma/imunologia , Vacúolos/enzimologia , Vacúolos/parasitologia , Animais , Western Blotting , Linhagem Celular , Eletroforese em Gel de Poliacrilamida , Imuno-Histoquímica , Camundongos
3.
Life Sci Alliance ; 4(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33858959

RESUMO

Tumor necrosis factor receptor 1 (TNFR1) activates NF-κB-dependent pro-inflammatory gene expression, but also induces cell death by triggering apoptosis and necroptosis. Inhibition of inhibitor of NF-κB kinase (IKK)/NF-κB signaling in keratinocytes paradoxically unleashed spontaneous TNFR1-mediated skin inflammation in mice, but the underlying mechanisms remain poorly understood. Here, we show that TNFR1 causes skin inflammation in mice with epidermis-specific knockout of IKK2 by inducing receptor interacting protein kinase 1 (RIPK1)-dependent necroptosis, and to a lesser extent also apoptosis, of keratinocytes. Combined epidermis-specific ablation of the NF-κB subunits RelA and c-Rel also caused skin inflammation by inducing TNFR1-mediated keratinocyte necroptosis. Contrary to the currently established model that inhibition of NF-κB-dependent gene transcription causes RIPK1-independent cell death, keratinocyte necroptosis, and skin inflammation in mice with epidermis-specific RelA and c-Rel deficiency also depended on RIPK1 kinase activity. These results advance our understanding of the mechanisms regulating TNFR1-induced cell death and identify RIPK1-mediated necroptosis as a potent driver of skin inflammation.


Assuntos
Queratinócitos/metabolismo , Necroptose/fisiologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Apoptose/fisiologia , Feminino , Quinase I-kappa B/metabolismo , Inflamação/metabolismo , Queratinócitos/patologia , Masculino , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , NF-kappa B/fisiologia , Necroptose/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais , Pele/metabolismo , Pele/patologia , Fator de Necrose Tumoral alfa/farmacologia
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