RESUMEN
Interleukin (IL)-17a has been highly conserved during evolution of the vertebrate immune system and widely studied in contexts of infection and autoimmunity. Studies suggest that IL-17a promotes behavioral changes in experimental models of autism and aggregation behavior in worms. Here, through a cellular and molecular characterization of meningeal γδ17 T cells, we defined the nearest central nervous system-associated source of IL-17a under homeostasis. Meningeal γδ T cells express high levels of the chemokine receptor CXCR6 and seed meninges shortly after birth. Physiological release of IL-17a by these cells was correlated with anxiety-like behavior in mice and was partially dependent on T cell receptor engagement and commensal-derived signals. IL-17a receptor was expressed in cortical glutamatergic neurons under steady state and its genetic deletion decreased anxiety-like behavior in mice. Our findings suggest that IL-17a production by meningeal γδ17 T cells represents an evolutionary bridge between this conserved anti-pathogen molecule and survival behavioral traits in vertebrates.
Asunto(s)
Ansiedad/etiología , Ansiedad/metabolismo , Interleucina-17/metabolismo , Neuronas/inmunología , Neuronas/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Animales , Ansiedad/psicología , Conducta Animal , Proliferación Celular , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiopatología , Modelos Animales de Enfermedad , Duramadre , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Interleucina-17/genética , Meninges/inmunología , Meninges/metabolismo , Ratones , Ratones Noqueados , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Transducción de Señal , TranscriptomaRESUMEN
Tissue macrophages have an embryonic origin and can be replenished in some tissues under steady-state conditions by blood monocytes. However, little is known about the residency and properties of infiltrating monocytes after an inflammatory challenge. The meninges of the central nervous system (CNS) are populated by a dense network of macrophages that act as resident immune sentinels. Here we show that, following lymphocytic choriomeningitis virus infection, resident meningeal macrophages (MMs) acquired viral antigen and interacted directly with infiltrating cytotoxic T lymphocytes, which led to macrophage depletion. Concurrently, the meninges were infiltrated by inflammatory monocytes that engrafted the meningeal niche and remained in situ for months after viral clearance. This engraftment led to interferon-γ-dependent functional changes in the pool of MMs, including loss of bacterial and immunoregulatory sensors. Collectively, these data indicate that peripheral monocytes can engraft the meninges after an inflammatory challenge, imprinting the compartment with long-term defects in immune function.
Asunto(s)
Sistema Nervioso Central/inmunología , Macrófagos/inmunología , Meningitis Viral/inmunología , Monocitos/inmunología , Animales , Inmunidad , Inflamación/inmunología , Interferón gamma/fisiología , Meninges/inmunología , RatonesRESUMEN
Self-reactive B cell progenitors are eliminated through central tolerance checkpoints, a process thought to be restricted to the bone marrow in mammals. Here, we identified a consecutive trajectory of B cell development in the meninges of mice and non-human primates. The meningeal B cells were located predominantly at the dural sinuses, where endothelial cells expressed essential niche factors to support B cell development. Parabiosis experiments together with lineage tracing showed that meningeal developing B cells were replenished continuously from hematopoietic stem cell (HSC)-derived progenitors via a circulation-independent route. Autoreactive immature B cells that recognized myelin oligodendrocyte glycoprotein (MOG), a central nervous system-specific antigen, were eliminated specifically from the meninges. Furthermore, genetic deletion of the Mog gene restored the self-reactive B cell population in the meninges. These findings identify the meninges as a distinct reservoir for B cell development, allowing in situ negative selection to ensure a locally non-self-reactive immune repertoire.
Asunto(s)
Células Dendríticas/inmunología , Células Madre Hematopoyéticas/fisiología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Meninges/inmunología , Células Plasmáticas/inmunología , Animales , Anticuerpos Neutralizantes/metabolismo , Antígeno B7-1/metabolismo , Antígenos CD28/metabolismo , Autorrenovación de las Células , Supervivencia Celular , Células Cultivadas , Humanos , Inmunidad Humoral , Memoria Inmunológica , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Ratones , Ratones Endogámicos C57BLRESUMEN
The eye, an anatomical extension of the central nervous system (CNS), exhibits many molecular and cellular parallels to the brain. Emerging research demonstrates that changes in the brain are often reflected in the eye, particularly in the retina1. Still, the possibility of an immunological nexus between the posterior eye and the rest of the CNS tissues remains unexplored. Here, studying immune responses to herpes simplex virus in the brain, we observed that intravitreal immunization protects mice against intracranial viral challenge. This protection extended to bacteria and even tumours, allowing therapeutic immune responses against glioblastoma through intravitreal immunization. We further show that the anterior and posterior compartments of the eye have distinct lymphatic drainage systems, with the latter draining to the deep cervical lymph nodes through lymphatic vasculature in the optic nerve sheath. This posterior lymphatic drainage, like that of meningeal lymphatics, could be modulated by the lymphatic stimulator VEGFC. Conversely, we show that inhibition of lymphatic signalling on the optic nerve could overcome a major limitation in gene therapy by diminishing the immune response to adeno-associated virus and ensuring continued efficacy after multiple doses. These results reveal a shared lymphatic circuit able to mount a unified immune response between the posterior eye and the brain, highlighting an understudied immunological feature of the eye and opening up the potential for new therapeutic strategies in ocular and CNS diseases.
Asunto(s)
Encéfalo , Ojo , Sistema Linfático , Animales , Femenino , Humanos , Masculino , Ratones , Conejos , Bacterias/inmunología , Encéfalo/anatomía & histología , Encéfalo/inmunología , Dependovirus/inmunología , Ojo/anatomía & histología , Ojo/inmunología , Glioblastoma/inmunología , Herpesvirus Humano 2/inmunología , Inyecciones Intravítreas , Sistema Linfático/anatomía & histología , Sistema Linfático/inmunología , Vasos Linfáticos/anatomía & histología , Vasos Linfáticos/inmunología , Macaca mulatta , Meninges/inmunología , Nervio Óptico/inmunología , Porcinos , Pez Cebra , Factor C de Crecimiento Endotelial Vascular/inmunología , Factor C de Crecimiento Endotelial Vascular/metabolismo , Factor C de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache1,2. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system, affecting more than 2.5 million people a year3-5. How pain and neuroimmune interactions impact meningeal antibacterial host defences are unclear. Here we show that Nav1.8+ nociceptors signal to immune cells in the meninges through the neuropeptide calcitonin gene-related peptide (CGRP) during infection. This neuroimmune axis inhibits host defences and exacerbates bacterial meningitis. Nociceptor neuron ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors through its pore-forming toxin pneumolysin to release CGRP from nerve terminals. CGRP acted through receptor activity modifying protein 1 (RAMP1) on meningeal macrophages to polarize their transcriptional responses, suppressing macrophage chemokine expression, neutrophil recruitment and dural antimicrobial defences. Macrophage-specific RAMP1 deficiency or pharmacological blockade of RAMP1 enhanced immune responses and bacterial clearance in the meninges and brain. Therefore, bacteria hijack CGRP-RAMP1 signalling in meningeal macrophages to facilitate brain invasion. Targeting this neuroimmune axis in the meninges can enhance host defences and potentially produce treatments for bacterial meningitis.
Asunto(s)
Encéfalo , Meninges , Meningitis Bacterianas , Neuroinmunomodulación , Humanos , Encéfalo/inmunología , Encéfalo/microbiología , Péptido Relacionado con Gen de Calcitonina/metabolismo , Meninges/inmunología , Meninges/microbiología , Meninges/fisiopatología , Dolor/etiología , Canal de Sodio Activado por Voltaje NAV1.8/metabolismo , Meningitis Bacterianas/complicaciones , Meningitis Bacterianas/inmunología , Meningitis Bacterianas/microbiología , Meningitis Bacterianas/patología , Streptococcus agalactiae/inmunología , Streptococcus agalactiae/patogenicidad , Streptococcus pneumoniae/inmunología , Streptococcus pneumoniae/patogenicidad , Nociceptores/metabolismo , Proteína 1 Modificadora de la Actividad de Receptores/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismoRESUMEN
To surveil an organ for pathogens, lymphoid structures need to sample antigens locally. The full set of lymphoid structures involved in surveilling for brain-tropic pathogens has not been defined. Through comprehensive imaging of the mouse meninges, a new study by Fitzpatrick et al. describes dural-associated lymphoid tissue (DALT) and its contribution to humoral responses following intranasal viral infection.
Asunto(s)
Tejido Linfoide , Animales , Tejido Linfoide/inmunología , Tejido Linfoide/virología , Humanos , Ratones , Meninges/inmunología , Encéfalo/inmunología , Encéfalo/virología , Encéfalo/fisiología , Inmunidad HumoralRESUMEN
Astrocytes are glial cells that are abundant in the central nervous system (CNS) and that have important homeostatic and disease-promoting functions1. However, little is known about the homeostatic anti-inflammatory activities of astrocytes and their regulation. Here, using high-throughput flow cytometry screening, single-cell RNA sequencing and CRISPR-Cas9-based cell-specific in vivo genetic perturbations in mice, we identify a subset of astrocytes that expresses the lysosomal protein LAMP12 and the death receptor ligand TRAIL3. LAMP1+TRAIL+ astrocytes limit inflammation in the CNS by inducing T cell apoptosis through TRAIL-DR5 signalling. In homeostatic conditions, the expression of TRAIL in astrocytes is driven by interferon-γ (IFNγ) produced by meningeal natural killer (NK) cells, in which IFNγ expression is modulated by the gut microbiome. TRAIL expression in astrocytes is repressed by molecules produced by T cells and microglia in the context of inflammation. Altogether, we show that LAMP1+TRAIL+ astrocytes limit CNS inflammation by inducing T cell apoptosis, and that this astrocyte subset is maintained by meningeal IFNγ+ NK cells that are licensed by the microbiome.
Asunto(s)
Astrocitos/inmunología , Microbioma Gastrointestinal/inmunología , Inflamación/prevención & control , Interferón gamma/inmunología , Células Asesinas Naturales/inmunología , Proteínas de Membrana de los Lisosomas/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Animales , Apoptosis , Astrocitos/metabolismo , Biomarcadores , Sistema Nervioso Central/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/prevención & control , Femenino , Homeostasis , Humanos , Inflamación/inmunología , Meninges/citología , Meninges/inmunología , Ratones , Ratones Endogámicos C57BL , Linfocitos T/citología , Linfocitos T/inmunologíaRESUMEN
Alzheimer's disease (AD) is the most prevalent cause of dementia1. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aß) is a promising therapeutic strategy2,3. Meningeal lymphatic drainage has an important role in the accumulation of Aß in the brain4, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aß passive immunotherapy by exacerbating the deposition of Aß, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aß by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunoterapia , Vasos Linfáticos/inmunología , Meninges/inmunología , Microglía/inmunología , Envejecimiento/efectos de los fármacos , Envejecimiento/inmunología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/efectos de los fármacos , Animales , Anticuerpos Monoclonales Humanizados/inmunología , Encéfalo/irrigación sanguínea , Encéfalo/citología , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Modelos Animales de Enfermedad , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/inmunología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Masculino , Meninges/irrigación sanguínea , Meninges/citología , Ratones , Microglía/citología , Microglía/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Factor C de Crecimiento Endotelial Vascular/metabolismo , Factor C de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
The central nervous system (CNS) and its meningeal coverings accommodate a diverse myeloid compartment that includes parenchymal microglia and perivascular macrophages, as well as choroid plexus and meningeal macrophages, dendritic cells, and granulocytes. These myeloid populations enjoy an intimate relationship with the CNS, where they play an essential role in both health and disease. Although the importance of these cells is clearly recognized, their exact function in the CNS continues to be explored. Here, we review the subsets of myeloid cells that inhabit the parenchyma, meninges, and choroid plexus and discuss their roles in CNS homeostasis. We also discuss the role of these cells in various neurological pathologies, such as autoimmunity, mechanical injury, neurodegeneration, and infection. We highlight the neuroprotective nature of certain myeloid cells by emphasizing their therapeutic potential for the treatment of neurological conditions.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Plexo Coroideo/inmunología , Infecciones/inmunología , Células Mieloides/fisiología , Enfermedades Neurodegenerativas/inmunología , Neuroinmunomodulación , Heridas y Lesiones/inmunología , Animales , Sistema Nervioso Central , Humanos , Meninges/inmunología , NeuroprotecciónRESUMEN
The central nervous system has historically been viewed as an immune-privileged site, but recent data have shown that the meninges-the membranes that surround the brain and spinal cord-contain a diverse population of immune cells1. So far, studies have focused on macrophages and T cells, but have not included a detailed analysis of meningeal humoral immunity. Here we show that, during homeostasis, the mouse and human meninges contain IgA-secreting plasma cells. These cells are positioned adjacent to dural venous sinuses: regions of slow blood flow with fenestrations that can potentially permit blood-borne pathogens to access the brain2. Peri-sinus IgA plasma cells increased with age and following a breach of the intestinal barrier. Conversely, they were scarce in germ-free mice, but their presence was restored by gut re-colonization. B cell receptor sequencing confirmed that meningeal IgA+ cells originated in the intestine. Specific depletion of meningeal plasma cells or IgA deficiency resulted in reduced fungal entrapment in the peri-sinus region and increased spread into the brain following intravenous challenge, showing that meningeal IgA is essential for defending the central nervous system at this vulnerable venous barrier surface.
Asunto(s)
Senos Craneales/inmunología , Microbioma Gastrointestinal/inmunología , Inmunoglobulina A Secretora/inmunología , Intestinos/inmunología , Meninges/inmunología , Células Plasmáticas/inmunología , Anciano , Envejecimiento/inmunología , Animales , Barrera Hematoencefálica/inmunología , Femenino , Hongos/inmunología , Vida Libre de Gérmenes , Humanos , Intestinos/citología , Intestinos/microbiología , Masculino , Meninges/irrigación sanguínea , Meninges/citología , Ratones , Ratones Endogámicos C57BL , Células Plasmáticas/citologíaRESUMEN
Immune surveillance against pathogens and tumours in the central nervous system is thought to be limited owing to the lack of lymphatic drainage. However, the characterization of the meningeal lymphatic network has shed light on previously unappreciated ways that an immune response can be elicited to antigens that are expressed in the brain1-3. Despite progress in our understanding of the development and structure of the meningeal lymphatic system, the contribution of this network in evoking a protective antigen-specific immune response in the brain remains unclear. Here, using a mouse model of glioblastoma, we show that the meningeal lymphatic vasculature can be manipulated to mount better immune responses against brain tumours. The immunity that is mediated by CD8 T cells to the glioblastoma antigen is very limited when the tumour is confined to the central nervous system, resulting in uncontrolled tumour growth. However, ectopic expression of vascular endothelial growth factor C (VEGF-C) promotes enhanced priming of CD8 T cells in the draining deep cervical lymph nodes, migration of CD8 T cells into the tumour, rapid clearance of the glioblastoma and a long-lasting antitumour memory response. Furthermore, transfection of an mRNA construct that expresses VEGF-C works synergistically with checkpoint blockade therapy to eradicate existing glioblastoma. These results reveal the capacity of VEGF-C to promote immune surveillance of tumours, and suggest a new therapeutic approach to treat brain tumours.
Asunto(s)
Neoplasias Encefálicas/inmunología , Glioblastoma/inmunología , Vigilancia Inmunológica/inmunología , Ganglios Linfáticos/inmunología , Vasos Linfáticos/inmunología , Factor C de Crecimiento Endotelial Vascular/metabolismo , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/inmunología , Línea Celular Tumoral , Movimiento Celular , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Reactividad Cruzada , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Células HEK293 , Humanos , Memoria Inmunológica/inmunología , Linfangiogénesis , Masculino , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Meninges/inmunología , Ratones , Ratones Endogámicos C57BL , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Factor C de Crecimiento Endotelial Vascular/administración & dosificación , Factor C de Crecimiento Endotelial Vascular/genética , Factor C de Crecimiento Endotelial Vascular/uso terapéuticoRESUMEN
Traumatic brain injury (TBI) is a major cause of disability and mortality worldwide, particularly among the elderly, yet our mechanistic understanding of what renders the post-traumatic brain vulnerable to poor outcomes, and susceptible to neurological disease, is incomplete. It is well established that dysregulated and sustained immune responses elicit negative consequences after TBI; however, our understanding of the neuroimmune interface that facilitates crosstalk between central and peripheral immune reservoirs is in its infancy. The meninges serve as the interface between the brain and the immune system, facilitating important bi-directional roles in both healthy and disease settings. It has been previously shown that disruption of this system exacerbates neuroinflammation in age-related neurodegenerative disorders such as Alzheimer's disease; however, we have an incomplete understanding of how the meningeal compartment influences immune responses after TBI. In this manuscript, we will offer a detailed overview of the holistic nature of neuroinflammatory responses in TBI, including hallmark features observed across clinical and animal models. We will highlight the structure and function of the meningeal lymphatic system, including its role in immuno-surveillance and immune responses within the meninges and the brain. We will provide a comprehensive update on our current knowledge of meningeal-derived responses across the spectrum of TBI, and identify new avenues for neuroimmune modulation within the neurotrauma field.
Asunto(s)
Lesiones Traumáticas del Encéfalo , Meninges , Enfermedades Neuroinflamatorias , Lesiones Traumáticas del Encéfalo/inmunología , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/patología , Humanos , Animales , Meninges/inmunología , Meninges/patología , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/etiología , Enfermedades Neuroinflamatorias/patología , Neuroinmunomodulación/fisiología , Neuroinmunomodulación/inmunologíaRESUMEN
Tertiary lymphoid tissues (TLTs) have been observed in the meninges of multiple sclerosis (MS) patients, but the stromal cells and molecular signals that support TLTs remain unclear. Here, we show that T helper 17 (Th17) cells induced robust TLTs within the brain meninges that were associated with local demyelination during experimental autoimmune encephalitis (EAE). Th17-cell-induced TLTs were underpinned by a network of stromal cells producing extracellular matrix proteins and chemokines, enabling leukocytes to reside within, rather than simply transit through, the meninges. Within the CNS, interactions between lymphotoxin αß (LTαß) on Th17 cells and LTßR on meningeal radio-resistant cells were necessary for the propagation of de novo interleukin-17 responses, and activated T cells from MS patients expressed elevated levels of LTßR ligands. Therefore, input from both Th17 cells and the lymphotoxin pathway induce the formation of an immune-competent stromal cell niche in the meninges.
Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Linfotoxina-alfa/inmunología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Células del Estroma/inmunología , Células Th17/inmunología , Adulto , Animales , Linfocitos T CD4-Positivos/inmunología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Inflamación/inmunología , Masculino , Meninges/citología , Meninges/inmunología , Ratones , Ratones Noqueados , Reacción en Cadena de la Polimerasa , Transducción de Señal/inmunologíaRESUMEN
Ectopic lymphoid tissue containing B cells forms in the meninges at late stages of human multiple sclerosis (MS) and when neuroinflammation is induced by interleukin (IL)-17 producing T helper (Th17) cells in rodents. B cell differentiation and the subsequent release of class-switched immunoglobulins have been speculated to occur in the meninges, but the exact cellular composition and underlying mechanisms of meningeal-dominated inflammation remain unknown. Here, we performed in-depth characterization of meningeal versus parenchymal Th17-induced rodent neuroinflammation. The most pronounced cellular and transcriptional differences between these compartments was the localization of B cells exhibiting a follicular phenotype exclusively to the meninges. Correspondingly, meningeal but not parenchymal Th17 cells acquired a B cell-supporting phenotype and resided in close contact with B cells. This preferential B cell tropism for the meninges and the formation of meningeal ectopic lymphoid tissue was partially dependent on the expression of the transcription factor Bcl6 in Th17 cells that is required in other T cell lineages to induce isotype class switching in B cells. A function of Bcl6 in Th17 cells was only detected in vivo and was reflected by the induction of B cell-supporting cytokines, the appearance of follicular B cells in the meninges, and of immunoglobulin class switching in the cerebrospinal fluid. We thus identify the induction of a B cell-supporting meningeal microenvironment by Bcl6 in Th17 cells as a mechanism controlling compartment specificity in neuroinflammation.
Asunto(s)
Enfermedades Neuroinflamatorias/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Células Th17/metabolismo , Animales , Linfocitos B/inmunología , Comunicación Celular , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Centro Germinal/inmunología , Inflamación/metabolismo , Activación de Linfocitos , Masculino , Meninges/inmunología , Meninges/metabolismo , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/metabolismo , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/fisiopatología , Tejido Parenquimatoso/inmunología , Tejido Parenquimatoso/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/fisiología , Células Th17/inmunología , Células Th17/fisiologíaRESUMEN
RATIONALE: The recent discovery of meningeal lymphatics in mammals is reshaping our understanding of fluid homeostasis and cellular waste management in the brain, but visualization and experimental analysis of these vessels is challenging in mammals. Although the optical clarity and experimental advantages of zebrafish have made this an essential model organism for studying lymphatic development, the existence of meningeal lymphatics has not yet been reported in this species. OBJECTIVE: Examine the intracranial space of larval, juvenile, and adult zebrafish to determine whether and where intracranial lymphatic vessels are present. METHODS AND RESULTS: Using high-resolution optical imaging of the meninges in living animals, we show that zebrafish possess a meningeal lymphatic network comparable to that found in mammals. We confirm that this network is separate from the blood vascular network and that it drains interstitial fluid from the brain. We document the developmental origins and growth of these vessels into a distinct network separated from the external lymphatics. Finally, we show that these vessels contain immune cells and perform live imaging of immune cell trafficking and transmigration in meningeal lymphatics. CONCLUSIONS: This discovery establishes the zebrafish as a important new model for experimental analysis of meningeal lymphatic development and opens up new avenues for probing meningeal lymphatic function in health and disease.
Asunto(s)
Linfangiogénesis , Vasos Linfáticos/fisiología , Meninges/fisiología , Microscopía Confocal , Imagen Óptica , Animales , Animales Modificados Genéticamente , Linfangiogénesis/efectos de los fármacos , Vasos Linfáticos/efectos de los fármacos , Vasos Linfáticos/inmunología , Meninges/inmunología , Infiltración Neutrófila , Neutrófilos/inmunología , Factor C de Crecimiento Endotelial Vascular/farmacología , Pez Cebra/genéticaRESUMEN
Multiple sclerosis (MS) is an idiopathic demyelinating disease in which meningeal inflammation correlates with accelerated disease progression. The study of meningeal inflammation in MS has been limited because of constrained access to MS brain/spinal cord specimens and the lack of experimental models recapitulating progressive MS. Unlike induced models, a spontaneously occurring model would offer a unique opportunity to understand MS immunopathogenesis and provide a compelling framework for translational research. We propose granulomatous meningoencephalomyelitis (GME) as a natural model to study neuropathological aspects of MS. GME is an idiopathic, progressive neuroinflammatory disease of young dogs with a female bias. In the GME cases examined in this study, the meninges displayed focal and disseminated leptomeningeal enhancement on magnetic resonance imaging, which correlated with heavy leptomeningeal lymphocytic infiltration. These leptomeningeal infiltrates resembled tertiary lymphoid organs containing large B cell clusters that included few proliferating Ki67+ cells, plasma cells, follicular dendritic/reticular cells, and germinal center B cell-like cells. These B cell collections were confined in a specialized network of collagen fibers associated with the expression of the lympho-organogenic chemokines CXCL13 and CCL21. Although neuroparenchymal perivascular infiltrates contained B cells, they lacked the immune signature of aggregates in the meningeal compartment. Finally, meningeal B cell accumulation correlated significantly with cortical demyelination reflecting neuropathological similarities to MS. Hence, during chronic neuroinflammation, the meningeal microenvironment sustains B cell accumulation that is accompanied by underlying neuroparenchymal injury, indicating GME as a novel, naturally occurring model to study compartmentalized neuroinflammation and the associated pathology thought to contribute to progressive MS.
Asunto(s)
Linfocitos B/inmunología , Modelos Animales de Enfermedad , Meninges/inmunología , Esclerosis Múltiple Crónica Progresiva/inmunología , Animales , Linfocitos B/patología , Perros , Meninges/patología , Esclerosis Múltiple Crónica Progresiva/patologíaRESUMEN
Platelets are best known for their vasoprotective responses to injury and inflammation. Here, we have asked whether they also support vascular integrity when neither injury nor inflammation is present. Changes in vascular barrier function in dermal and meningeal vessels were measured in real time in mouse models using the differential extravasation of fluorescent tracers as a biomarker. Severe thrombocytopenia produced by two distinct methods caused increased extravasation of 40-kDa dextran from capillaries and postcapillary venules but had no effect on extravasation of 70-kDa dextran or albumin. This reduction in barrier function required more than 4 h to emerge after thrombocytopenia was established, reverting to normal as the platelet count recovered. Barrier dysfunction was also observed in mice that lacked platelet-dense granules, dense granule secretion machinery, glycoprotein (GP) VI, or the GPVI signaling effector phospholipase C (PLC) γ2. It did not occur in mice lacking α-granules, C type lectin receptor-2 (CLEC-2), or protease activated receptor 4 (PAR4). Notably, although both meningeal and dermal vessels were affected, intracerebral vessels, which are known for their tighter junctions between endothelial cells, were not. Collectively, these observations 1) highlight a role for platelets in maintaining vascular homeostasis in the absence of injury or inflammation, 2) provide a sensitive biomarker for detecting changes in platelet-dependent barrier function, 3) identify which platelet processes are required, and 4) suggest that the absence of competent platelets causes changes in the vessel wall itself, accounting for the time required for dysfunction to emerge.
Asunto(s)
Plaquetas/inmunología , Vasos Sanguíneos/inmunología , Hemostasis , Homeostasis , Animales , Vasos Sanguíneos/lesiones , Vasos Sanguíneos/fisiopatología , Femenino , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Masculino , Meninges/irrigación sanguínea , Meninges/inmunología , Ratones , Fosfolipasa C gamma/genética , Fosfolipasa C gamma/inmunología , Piel/irrigación sanguínea , Piel/inmunologíaRESUMEN
Monocyte-derived macrophages are essential for recovery after spinal cord injury, but their homing mechanism is poorly understood. Here, we show that although of common origin, the homing of proinflammatory (M1) and the "alternatively activated" anti-inflammatory (M2) macrophages to traumatized spinal cord (SC) was distinctly regulated, neither being through breached blood-brain barrier. The M1 macrophages (Ly6c(hi)CX3CR1(lo)) derived from monocytes homed in a CCL2 chemokine-dependent manner through the adjacent SC leptomeninges. The resolving M2 macrophages (Ly6c(lo)CX3CR1(hi)) derived from monocytes trafficked through a remote blood-cerebrospinal-fluid (CSF) barrier, the brain-ventricular choroid plexus (CP), via VCAM-1-VLA-4 adhesion molecules and epithelial CD73 enzyme for extravasation and epithelial transmigration. Blockage of these determinants, or mechanical CSF flow obstruction, inhibited M2 macrophage recruitment and impaired motor-function recovery. The CP, along with the CSF and the central canal, provided an anti-inflammatory supporting milieu, potentially priming the trafficking monocytes. Overall, our finding demonstrates that the route of monocyte entry to central nervous system provides an instructional environment to shape their function.
Asunto(s)
Plexo Coroideo/inmunología , Macrófagos/inmunología , Traumatismos de la Médula Espinal/inmunología , Médula Espinal/inmunología , 5'-Nucleotidasa/antagonistas & inhibidores , 5'-Nucleotidasa/genética , 5'-Nucleotidasa/inmunología , Adenosina Difosfato/análogos & derivados , Adenosina Difosfato/farmacología , Animales , Antígenos Ly/inmunología , Antígenos Ly/metabolismo , Barrera Hematoencefálica/inmunología , Barrera Hematoencefálica/metabolismo , Receptor 1 de Quimiocinas CX3C , Movimiento Celular/genética , Movimiento Celular/inmunología , Plexo Coroideo/metabolismo , Inhibidores Enzimáticos/farmacología , Citometría de Flujo , Expresión Génica/inmunología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Integrina alfa4beta1/genética , Integrina alfa4beta1/inmunología , Antígenos Comunes de Leucocito/inmunología , Antígenos Comunes de Leucocito/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Meninges/inmunología , Meninges/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Monocitos/efectos de los fármacos , Monocitos/inmunología , Monocitos/metabolismo , Receptores de Quimiocina/genética , Receptores de Quimiocina/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/líquido cefalorraquídeo , Traumatismos de la Médula Espinal/genética , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/inmunologíaRESUMEN
At steady state, the CNS parenchyma has few to no lymphocytes and less potent Ag-presentation capability compared with other organs. However, the meninges surrounding the CNS host diverse populations of immune cells that influence how CNS-related immune responses develop. Interstitial and cerebrospinal fluid produced in the CNS is continuously drained, and recent advances have emphasized that this process is largely taking place through the lymphatic system. To what extent this fluid process mobilizes CNS-derived Ags toward meningeal immune cells and subsequently the peripheral immune system through the lymphatic vessel network is a question of significant clinical importance for autoimmunity, tumor immunology, and infectious disease. Recent advances in understanding the role of meningeal lymphatics as a communicator between the brain and peripheral immunity are discussed in this review.
Asunto(s)
Encéfalo/inmunología , Vigilancia Inmunológica/inmunología , Vasos Linfáticos , Meninges/inmunología , Animales , Sistema Nervioso Central/inmunología , HumanosRESUMEN
Meningeal B lymphocyte aggregates have been described in autopsy material of patients with chronic multiple sclerosis. The presence of meningeal B cell aggregates has been correlated with worse disease. However, the functional role of these meningeal B cell aggregates is not understood. Here, we use a mouse model of multiple sclerosis, the spontaneous opticospinal encephalomyelitis model, which is built on the double transgenic expression of myelin oligodendrocyte glycoprotein-specific T-cell and B-cell receptors, to show that the formation of meningeal B cell aggregates is dependent on the expression of α4 integrins by antigen-specific T cells. T cell-conditional genetic ablation of α4 integrins in opticospinal encephalomyelitis mice impaired the formation of meningeal B cell aggregates, and surprisingly, led to a higher disease incidence as compared to opticospinal encephalomyelitis mice with α4 integrin-sufficient T cells. B cell-conditional ablation of α4 integrins in opticospinal encephalomyelitis mice resulted in the entire abrogation of the formation of meningeal B cell aggregates, and opticospinal encephalomyelitis mice with α4 integrin-deficient B cells suffered from a higher disease burden than regular opticospinal encephalomyelitis mice. While anti-CD20 antibody-mediated systemic depletion of B cells in opticospinal encephalomyelitis mice after onset of disease failed to efficiently decrease meningeal B cell aggregates without significantly modulating disease progression, treatment with anti-CD19 chimeric antigen receptor-T cells eliminated meningeal B cell aggregates and exacerbated clinical disease in opticospinal encephalomyelitis mice. Since about 20% of B cells in organized meningeal B cell aggregates produced either IL-10 or IL-35, we propose that meningeal B cell aggregates might also have an immunoregulatory function as to the immunopathology in adjacent spinal cord white matter. The immunoregulatory function of meningeal B cell aggregates needs to be considered when designing highly efficient therapies directed against meningeal B cell aggregates for clinical application in multiple sclerosis.