RESUMO
Psoriasis is mainly caused because of inappropriate immune responses in the epidermis. Rice (Oryza sativa L.: SRNC05053-6-2) consists of anthocyanin, which exhibits strong antioxidative and anti-inflammatory properties. This study aimed to evaluate the role of this black-coloured rice crude extract in alleviating the symptoms of psoriasis using human psoriatic artificial skin and an imiquimod-induced rat psoriasis model. Psoriasis-related genes, cytokines and chemokines were examined; in addition, the antioxidative and anti-inflammatory properties and the immunohistopathological features of this condition were studied. The results showed that the rice extract reduced the severity of psoriasis by (1) decreasing the epidermal thickness, acanthosis, hyperkeratosis, epidermal inflammation and degree of apoptosis induction via caspase-3, (2) increasing the expression levels of anti-inflammatory cytokines (IL-10 and TGF-ß), (3) reducing the levels of pro-inflammatory cytokines (IL-6, IL-8, IL-20, IL-22 and TNF-α), chemokines (CCL-20) and anti-microbial peptides (psoriasin and ß-defensin), (4) enhancing the antioxidative property (Nrf-2), (5) downregulating the levels of psoriasis-associated genes (psoriasin, ß-defensin, koebnerisin 15L and koebnerisin 15S) and (6) upregulating the levels of psoriasis-improving genes (caspase-14, involucrin and filaggrin). Thus, the extract appears to exert therapeutic effects on psoriasis through its antioxidative and immunomodulatory properties.
Assuntos
Antioxidantes/uso terapêutico , Epiderme/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Psoríase/tratamento farmacológico , Pele/efeitos dos fármacos , Animais , Antioxidantes/administração & dosagem , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Epiderme/metabolismo , Proteínas Filagrinas , Humanos , Imiquimode , Oryza , Extratos Vegetais/administração & dosagem , Psoríase/induzido quimicamente , Psoríase/metabolismo , Ratos , Ratos Sprague-Dawley , Proteína A7 Ligante de Cálcio S100/metabolismo , Pele/metabolismo , Pele Artificial , Resultado do TratamentoRESUMO
Skin models mimicking features of psoriasis-related inflammation are needed to support the development of new drugs in dermatology. Reconstructed skin models lack tissue complexity, including a fully competent skin barrier, and presence and/or diversity of immune cells. Here, we describe InflammaSkin®, a novel human Th17-driven ex vivo skin inflammation model. In this model, skin-resident T cells are in situ activated by intradermal injection of anti-CD3 and anti-CD28 antibodies and Th17 cell polarization is sustained by culture in a chemically defined medium supplemented with IL-1ß, IL-23 and TGF-ß for seven days. The acquired Th17 signature is demonstrated by the sustained secretion of IL-17A, IL-17AF, IL-17F, IL-22, IFN-γ, and to some degree IL-15 and TNF-α observed in the activated ex vivo skin inflammation model compared with the non-activated skin model control. Furthermore, expression of S100A7 and Keratin-16 by keratinocytes and loss of epidermal structure integrity occur subsequently to in situ Th17cell activation, demonstrating cellular crosstalk between Th17 cells and keratinocytes. Finally, we demonstrate the use of this model to investigate the modulation of the IL-23/IL-17 immune axis by topically applied anti-inflammatory compounds. Taken together, we show that by in situ activation of skin-resident Th17 cells, the InflammaSkin® model reproduces aspects of inflammatory responses observed in psoriatic lesions and could be used as a translational tool to assess efficacy of test compounds.
Assuntos
Dermatite/imunologia , Ativação Linfocitária , Modelos Biológicos , Células Th17/imunologia , Anti-Inflamatórios/uso terapêutico , Anticorpos , Betametasona/análogos & derivados , Betametasona/uso terapêutico , Antígenos CD28/imunologia , Complexo CD3/imunologia , Comunicação Celular , Meios de Cultura , Dermatite/tratamento farmacológico , Humanos , Interferon gama/metabolismo , Interleucina-15/metabolismo , Interleucina-17/metabolismo , Interleucinas/metabolismo , Queratina-16/metabolismo , Queratinócitos/metabolismo , Inibidores da Fosfodiesterase 4/uso terapêutico , Proteína A7 Ligante de Cálcio S100/metabolismo , Células Th17/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina 22Assuntos
Benzoxazóis/farmacologia , Butiratos/farmacologia , Queratinócitos/efeitos dos fármacos , Psoríase/tratamento farmacológico , Proteína A7 Ligante de Cálcio S100/antagonistas & inibidores , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , PPAR alfa/agonistas , PPAR alfa/metabolismo , Psoríase/imunologia , Psoríase/patologia , Proteína A7 Ligante de Cálcio S100/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Antimicrobial peptides (AMPs) are the body's natural innate immune defense against a spectrum of pathogens and can also modulate cell proliferation, chemotaxis, angiogenesis, wound healing, and immune cell activity. Harnessing these diverse functions for prophylactic use is contingent upon understanding the regulatory mechanisms governing their unconventional secretion from cells. Analysis of the secretion of S100A7 (Psoriasin), an abundant AMP stored in differentiated keratinocytes of the skin, has revealed an unexpected biphasic secretory response to bacterial exposure. The core components regulating S100A7 secretion are NFκB/p38MAPK, caspase-1, and interleukin (IL)-1α. The initial activation of this core machinery is mediated by Toll-like receptor signaling, whereas the chronic response is mediated by Caspase-8 downregulation. Interestingly, there is a concomitant downregulation of Caspase-8 in inflammatory skin diseases wherein S100A7 is constitutively released. These results highlight the potential of targeting these components to control the release of AMPs from the skin in both homeostatic and disease conditions.