RESUMO
Interferon regulatory factor 5 (IRF5) is a master regulator of macrophage phenotype and a key transcription factor involved in expression of proinflammatory cytokine responses to microbial and viral infection. Here, we show that IRF5 controls cellular and metabolic responses. By integrating ChIP sequencing (ChIP-Seq) and assay for transposase-accessible chromatin using sequencing (ATAC)-seq data sets, we found that IRF5 directly regulates metabolic genes such as hexokinase-2 (Hk2). The interaction of IRF5 and metabolic genes had a functional consequence, as Irf5-/- airway macrophages but not bone marrow-derived macrophages (BMDMs) were characterized by a quiescent metabolic phenotype at baseline and had reduced ability to utilize oxidative phosphorylation after Toll-like receptor (TLR)-3 activation, in comparison to controls, ex vivo. In a murine model of influenza infection, IRF5 deficiency had no effect on viral load in comparison to wild-type controls but controlled metabolic responses to viral infection, as IRF5 deficiency led to reduced expression of Sirt6 and Hk2. Together, our data indicate that IRF5 is a key component of AM metabolic responses following influenza infection and TLR-3 activation.
Assuntos
Metabolismo Energético/imunologia , Regulação da Expressão Gênica/imunologia , Fatores Reguladores de Interferon/imunologia , Macrófagos/imunologia , Sistema Respiratório/citologia , Animais , Células Cultivadas , Sequenciamento de Cromatina por Imunoprecipitação/métodos , Metabolismo Energético/genética , Feminino , Hexoquinase/genética , Hexoquinase/imunologia , Hexoquinase/metabolismo , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sirtuínas/genética , Sirtuínas/imunologia , Sirtuínas/metabolismo , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/imunologia , Receptor 3 Toll-Like/metabolismoRESUMO
In vitro studies have shown that SCAR/WAVE activates the Arp2/3 complex to generate actin filaments, which in many cell types are organised into lamellipodia that are thought to have an important role in cell migration. Here we demonstrate that SCAR is utilised by Drosophila macrophages to drive their developmental and inflammatory migrations and that it is regulated via the Hem/Kette/Nap1-containing SCAR/WAVE complex. SCAR is also important in protecting against bacterial pathogens and in wound repair as SCAR mutant embryos succumb more readily to both sterile and infected wounds. However, in addition to driving the formation of lamellipodia in macrophages, SCAR is required cell autonomously for the correct processing of phagocytosed apoptotic corpses by these professional phagocytes. Removal of this phagocytic burden by preventing apoptosis rescues macrophage lamellipodia formation and partially restores motility. Our results show that efficient processing of phagosomes is critical for effective macrophage migration in vivo. These findings have important implications for the resolution of macrophages from chronic wounds and the behaviour of those associated with tumours, because phagocytosis of debris may serve to prolong the presence of these cells at these sites of pathology.
Assuntos
Apoptose , Proteínas de Drosophila/metabolismo , Macrófagos/fisiologia , Proteínas dos Microfilamentos/metabolismo , Fagocitose , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/ultraestrutura , Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo , Animais , Movimento Celular , Drosophila/fisiologia , Fagossomos/metabolismo , Pseudópodes/metabolismo , Pseudópodes/ultraestrutura , Transdução de SinaisRESUMO
In 14 patients, kyphoscoliotics, at the time without cardiorespiratory diseases, of average age 28 years +/- 17 (range 12-64), the average values for the vital capacity was 79.6 +/- 21.2% (range 49-125), for the Tiffeneau Index was 77.9% +/- 10.3% (range 56-91), for the RV/TLC ratio was 39.6% +/- 10.8% (range 18-56), for the MEF 25 was 2,192.8 +/- 732.1 ml/s (range 1,300-3,800), for the MEF 50 was 3,689.3 +/- 1,310.9 ml/s (range 1,750-5,500). The average value for the PaO2 was 90.3 +/- 8.3 mm Hg (range 75-109), and for the PaCO2 35.3 +/- 4.66 mm Hg (range 27.8-46). The average value for the alveolar-arterial gradient of O2 was 11.96 +/- 7.37 mm Hg (range 0.74-27.94) and for the arterial-alveolar gradient of CO2 2.30 +/- 2.41 mm Hg (range 0.22-9.98). The average value for the CO transfer was 20.06 +/- 6.84 ml/min/mm Hg (range 8-31.4). As the angle of scoliosis and the age of the subject increase, the vital capacity and the Tiffeneau Index decrease, the RV/TLC ratio and the respiratory rate increase, the MEF 25, the MEF 50, the PaO2, and the transfer of CO decrease, while PaCO2 increases. The alveolar-arterial gradient of O2 and the arterial-alveolar gradient of CO2 increase as the angle of scoliosis increases. The data so obtained show, therefore, that in kyphoscoliosis a restrictive type of respiratory dysfunction appears, along with hypoxemia due to alveolar hypoventilation and disturbances in diffusion and in the ventilation-perfusion ratio.