RESUMO
A20 is a ubiquitin-modifying protein that negatively regulates NF-κB signaling. Mutations in A20/TNFAIP3 are associated with a variety of autoimmune diseases, including multiple sclerosis (MS). We found that deletion of A20 in central nervous system (CNS) endothelial cells (ECs) enhances experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. A20ΔCNS-EC mice showed increased numbers of CNS-infiltrating immune cells during neuroinflammation and in the steady state. While the integrity of the blood-brain barrier (BBB) was not impaired, we observed a strong activation of CNS-ECs in these mice, with dramatically increased levels of the adhesion molecules ICAM-1 and VCAM-1. We discovered ICOSL to be expressed by A20-deficient CNS-ECs, which we found to function as adhesion molecules. Silencing of ICOSL in CNS microvascular ECs partly reversed the phenotype of A20ΔCNS-EC mice without reaching statistical significance and delayed the onset of EAE symptoms in WT mice. In addition, blocking of ICOSL on primary mouse brain microvascular ECs impaired the adhesion of T cells in vitro. Taken together, we propose that CNS EC-ICOSL contributes to the firm adhesion of T cells to the BBB, promoting their entry into the CNS and eventually driving neuroinflammation.
Assuntos
Encefalomielite Autoimune Experimental , Doenças Neuroinflamatórias , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Animais , Camundongos , Barreira Hematoencefálica/metabolismo , Sistema Nervoso Central/metabolismo , Células Endoteliais/metabolismo , Camundongos Endogâmicos C57BL , Esclerose Múltipla/metabolismo , Doenças Neuroinflamatórias/metabolismo , Linfócitos T/metabolismo , Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismoRESUMO
Chronic stress is a major risk factor for developing psychiatric conditions. In addition to elevating the levels of stress hormones released in the body, chronic stress activates the immune system, resulting in increased levels of proinflammatory cytokines and innate immune cells in the circulation of rodents and humans. Furthermore, exposure to chronic stress alters the phenotype of microglia, a population of innate immune cells that reside in the CNS parenchyma. In rodent models, chronic stress activates microglia in defined brain regions and induces changes in their phenotype and functional properties. In this review, we discussed how microglia are activated in stressful situations. Furthermore, we described how microglia affect the CNS environment during chronic stress, through the production of cytokines, the induction of reactive oxygen species, and phagocytosis. We suggested that, due to their strategic location as immune cells within the CNS, microglia are important players in the induction of psychopathologies after chronic stress.
Assuntos
Citocinas , Microglia , Humanos , Fagocitose , Espécies Reativas de OxigênioRESUMO
Aircraft noise induces vascular and cerebral inflammation and oxidative stress causing hypertension and cardiovascular/cerebral dysfunction. With the present studies, we sought to determine the role of myeloid cells in the vascular vs. cerebral consequences of exposure to aircraft noise. Toxin-mediated ablation of lysozyme M+ (LysM+) myeloid cells was performed in LysMCreiDTR mice carrying a cre-inducible diphtheria toxin receptor. In the last 4d of toxin treatment, the animals were exposed to noise at maximum and mean sound pressure levels of 85 and 72 dB(A), respectively. Flow cytometry analysis revealed accumulation of CD45+, CD11b+, F4/80+, and Ly6G-Ly6C+ cells in the aortas of noise-exposed mice, which was prevented by LysM+ cell ablation in the periphery, whereas brain infiltrates were even exacerbated upon ablation. Aircraft noise-induced increases in blood pressure and endothelial dysfunction of the aorta and retinal/mesenteric arterioles were almost completely normalized by ablation. Correspondingly, reactive oxygen species in the aorta, heart, and retinal/mesenteric vessels were attenuated in ablated noise-exposed mice, while microglial activation and abundance in the brain was greatly increased. Expression of phagocytic NADPH oxidase (NOX-2) and vascular cell adhesion molecule-1 (VCAM-1) mRNA in the aorta was reduced, while NFκB signaling appeared to be activated in the brain upon ablation. In sum, we show dissociation of cerebral and peripheral inflammatory reactions in response to aircraft noise after LysM+ cell ablation, wherein peripheral myeloid inflammatory cells represent a dominant part of the pathomechanism for noise stress-induced cardiovascular effects and their central nervous counterparts, microglia, as key mediators in stress responses.
Assuntos
Artérias/enzimologia , Encéfalo/enzimologia , Encefalite/prevenção & controle , Microglia/enzimologia , Muramidase/deficiência , Células Mieloides/enzimologia , Ruído dos Transportes/efeitos adversos , Doenças Vasculares Periféricas/prevenção & controle , Aeronaves , Animais , Artérias/fisiopatologia , Encéfalo/patologia , Modelos Animais de Doenças , Encefalite/enzimologia , Encefalite/etiologia , Encefalite/patologia , Deleção de Genes , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/patologia , Muramidase/genética , Estresse Oxidativo , Doenças Vasculares Periféricas/enzimologia , Doenças Vasculares Periféricas/etiologia , Doenças Vasculares Periféricas/fisiopatologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
The innate immune cell compartment is highly diverse in the healthy central nervous system (CNS), including parenchymal and non-parenchymal macrophages. However, this complexity is increased in inflammatory settings by the recruitment of circulating myeloid cells. It is unclear which disease-specific myeloid subsets exist and what their transcriptional profiles and dynamics during CNS pathology are. Combining deep single-cell transcriptome analysis, fate mapping, in vivo imaging, clonal analysis, and transgenic mouse lines, we comprehensively characterized unappreciated myeloid subsets in several CNS compartments during neuroinflammation. During inflammation, CNS macrophage subsets undergo self-renewal, and random proliferation shifts toward clonal expansion. Last, functional studies demonstrated that endogenous CNS tissue macrophages are redundant for antigen presentation. Our results highlight myeloid cell diversity and provide insights into the brain's innate immune system.
Assuntos
Sistema Nervoso Central/imunologia , Imunidade Inata , Inflamação/imunologia , Macrófagos/citologia , Células Mieloides/citologia , Animais , Apresentação de Antígeno , Encéfalo/imunologia , Células Dendríticas/citologia , Encefalomielite Autoimune Experimental/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Homeostase , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos/citologia , Células Mieloides/imunologia , Análise de Sequência de RNA , Análise de Célula Única , Linfócitos T/imunologiaRESUMO
Rotaviruses are well-known causative agents of enteric disorders in humans and other mammals, but little is known about their virulence and pathogenic role in pigeons and other birds. Starting in summer 2017, a series of outbreaks of an acute disease with high mortalities was reported in domestic pigeons in Germany, Belgium and Denmark. The clinical picture was characterized by diarrhoea, vomiting, hepatic necrosis and sudden fatalities. From these severe outbreaks, we discovered several previously unknown group A rotavirus (RVA) lineages of genotype G18P[17]-I4-R4-C4-M4-A4-T4-N4-E19-H4, which were closely related but not identical to an RVA variant identified in cases of fatal hepatic necrosis in Australian pigeon lofts in 2016. Retrospective analysis demonstrated that the predecessors of the highly virulent variants have circulated in Europe since at least 2010. Our data indicate that reassortment and intercontinental spread has led to the emergence of novel RVA variants, which may constitute a major threat to animal welfare and health of domestic pigeon populations worldwide.