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1.
J Exp Med ; 218(11)2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34529751

RESUMO

Intestinal epithelial cell (IEC) NF-κB signaling regulates the balance between mucosal homeostasis and inflammation. It is not fully understood which signals tune this balance and how bacterial exposure elicits the process. Pure LPS induces epithelial NF-κB activation in vivo. However, we found that in mice, IECs do not respond directly to LPS. Instead, tissue-resident lamina propria intercrypt macrophages sense LPS via TLR4 and rapidly secrete TNF to elicit epithelial NF-κB signaling in their immediate neighborhood. This response pattern is relevant also during oral enteropathogen infection. The macrophage-TNF-IEC axis avoids responses to luminal microbiota LPS but enables crypt- or tissue-scale epithelial NF-κB responses in proportion to the microbial threat. Thereby, intercrypt macrophages fulfill important sentinel functions as first responders to Gram-negative microbes breaching the epithelial barrier. The tunability of this crypt response allows the induction of defense mechanisms at an appropriate scale according to the localization and intensity of microbial triggers.


Assuntos
Antibacterianos/metabolismo , Células Epiteliais/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/metabolismo , NF-kappa B/metabolismo , Fatores de Necrose Tumoral/metabolismo , Animais , Regulação da Expressão Gênica/fisiologia , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/fisiologia
2.
Cell Host Microbe ; 20(2): 238-49, 2016 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-27453483

RESUMO

Salmonella Typhimurium (S.Tm) causes acute enteropathy resolving after 4-7 days. Strikingly, antibiotic therapy does not accelerate disease resolution. We screened for factors blocking remission using a S.Tm enterocolitis model. The antibiotic ciprofloxacin clears pathogen stool loads within 3-24 hr, while gut pathology resolves more slowly (ψ50: ∼48 hr, remission: 6-9 days). This delayed resolution is mediated by an interferon-γ (IFN-γ)-dependent response that is triggered during acute infection and continues throughout therapy. Specifically, IFN-γ production by mucosal T and NK cells retards disease resolution by maintaining signaling through the transcriptional regulator STAT1 and boosting expression of inflammatory mediators like IL-1ß, TNF, and iNOS. Additionally, sustained IFN-γ fosters phagocyte accumulation and hampers antimicrobial defense mediated by IL-22 and the lectin REGIIIß. These findings reveal a role for IFN-γ in delaying resolution of intestinal inflammation and may inform therapies for acute Salmonella enteropathy, chronic inflammatory bowel diseases, or disease resolution during antibiotic treatment.


Assuntos
Antibacterianos/administração & dosagem , Enterocolite/patologia , Trato Gastrointestinal/patologia , Interferon gama/metabolismo , Infecções por Salmonella/patologia , Salmonella typhimurium/crescimento & desenvolvimento , Animais , Modelos Animais de Doenças , Enterocolite/tratamento farmacológico , Enterocolite/imunologia , Enterocolite/microbiologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Fatores Imunológicos/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Células Matadoras Naturais/imunologia , Camundongos Endogâmicos C57BL , Fagócitos/imunologia , Infecções por Salmonella/tratamento farmacológico , Infecções por Salmonella/imunologia , Infecções por Salmonella/microbiologia , Salmonella typhimurium/efeitos dos fármacos , Transdução de Sinais , Linfócitos T/imunologia
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