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1.
Gut Microbes ; 11(4): 771-788, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31941397

RESUMO

Type-I interferon (IFN-I) cytokines are produced by immune cells in response to microbial infections, cancer and autoimmune diseases, and subsequently, trigger cytoprotective and antiviral responses through the activation of IFN-I stimulated genes (ISGs). The ability of intestinal microbiota to modulate innate immune responses is well known, but the mechanisms underlying such responses remain elusive. Here we report that the intracellular sensors stimulator of IFN genes (STING) and mitochondrial antiviral signaling (MAVS) are essential for the production of IFN-I in response to lactic acid bacteria (LAB), common gut commensal bacteria with beneficial properties. Using human macrophage cells we show that LAB strains that potently activate the inflammatory transcription factor NF-κB are poor inducers of IFN-I and conversely, those triggering significant amounts of IFN-I fail to activate NF-κB. This IFN-I response is also observed in human primary macrophages, which modulate CD64 and CD40 upon challenge with IFN-I-inducing LAB. Mechanistically, IFN-I inducers interact more intimately with phagocytes as compared to NF-κB-inducers, and fail to activate IFN-I in the presence of phagocytosis inhibitors. These bacteria are then sensed intracellularly by the cytoplasmic sensors STING and, to a lesser extent, MAVS. Accordingly, macrophages deficient for STING showed dramatically reduced phosphorylation of TANK-binding kinase (TBK)-1 and IFN-I activation, which resulted in lower expression of ISGs. Our findings demonstrate a major role for intracellular sensing and STING in the production of IFN-I by beneficial bacteria and the existence of bacteria-specific immune signatures, which can be exploited to promote cytoprotective responses and prevent overreactive NF-κB-dependent inflammation in the gut.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Interferon Tipo I/biossíntese , Lactobacillales/fisiologia , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Humanos , Imunidade Inata , Lactobacillales/imunologia , Lactobacillus plantarum/imunologia , Lactobacillus plantarum/fisiologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/microbiologia , Macrófagos/imunologia , Macrófagos/microbiologia , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/microbiologia , NF-kappa B/metabolismo , Pediococcus pentosaceus/imunologia , Pediococcus pentosaceus/fisiologia , Fagocitose , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Células THP-1
2.
Immunol Rev ; 262(1): 36-55, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25319326

RESUMO

During development and throughout adult life, macrophages derived from hematopoietic progenitors are seeded throughout the body, initially in the absence of inflammatory and infectious stimuli as tissue-resident cells, with enhanced recruitment, activation, and local proliferation following injury and pathologic insults. We have learned a great deal about macrophage properties ex vivo and in cell culture, but their phenotypic heterogeneity within different tissue microenvironments remains poorly characterized, although it contributes significantly to maintaining local and systemic homeostasis, pathogenesis, and possible treatment. In this review, we summarize the nature, functions, and interactions of tissue macrophage populations within their microenvironment and suggest questions for further investigation.


Assuntos
Macrófagos/fisiologia , Fenótipo , Animais , Diferenciação Celular , Genômica , Homeostase , Humanos , Macrófagos/citologia , Monócitos/citologia , Monócitos/fisiologia , Especificidade de Órgãos
3.
Invest Ophthalmol Vis Sci ; 54(9): 5959-70, 2013 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-23927892

RESUMO

PURPOSE: Laser-induced choroidal neovascularization (CNV) is a widely used model to mimic many features of CNV resulting from wet AMD. Macrophages have been implicated in the pathogenesis of AMD. Class A scavenger receptors, scavenger receptor-A (SR-A) and macrophage receptor with collagenous domain (MARCO), are expressed on macrophages and are associated with macrophage function. The goal of this study is to examine the role of macrophage scavenger receptors in immune cell recruitment and the formation of CNV. METHODS: Laser photocoagulation was performed in wild-type and knockout mice with deletion of SR-A (SR-A(-/-)), MARCO (MARCO(-/-)), or both SR-A and MARCO double knockout (DKO). Immune cell recruitment at different time points and CNV lesions at 14 days after laser treatment were evaluated through immunostaining and confocal microscopy. Microarray analysis was performed in eyes 1 day after laser injury. RESULTS: Wild-type eyes showed higher chemokine/receptor expression compared with knockout eyes after laser injury. Scavenger receptor deficiency markedly impaired the recruitment of neutrophils and macrophages to CNV lesions at 1- and 3-days post laser injury, respectively. Significantly reduced CNV volumes were found in the eyes from scavenger receptor knockout mice compared with wild-type mice. CONCLUSIONS: The deficiency of scavenger receptors impairs the formation of CNV and immune cell recruitment. Our findings suggest a potential role for scavenger receptors in contributing to CNV formation and inflammation in AMD.


Assuntos
Neovascularização de Coroide/metabolismo , Macrófagos/metabolismo , Receptores Depuradores/fisiologia , Receptores Depuradores Classe A/fisiologia , Animais , Neovascularização de Coroide/etiologia , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Angiofluoresceinografia , Fundo de Olho , Imuno-Histoquímica , Lasers/efeitos adversos , Macrófagos/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Microscopia Confocal , Microscopia Eletrônica
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