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1.
Neuron ; 109(22): 3609-3618.e9, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34793707

RESUMO

Mechanisms governing how immune cells and their derived molecules impact homeostatic brain function are still poorly understood. Here, we elucidate neuronal mechanisms underlying T cell effects on synaptic function and episodic memory. Depletion of CD4 T cells led to memory deficits and impaired long-term potentiation. Severe combined immune-deficient mice exhibited amnesia, which was reversible by repopulation with T cells from wild-type but not from IL-4-knockout mice. Behaviors impacted by T cells were mediated via IL-4 receptors expressed on neurons. Exploration of snRNA-seq of neurons participating in memory processing provided insights into synaptic organization and plasticity-associated pathways regulated by immune cells. IL-4Rα knockout in inhibitory (but not in excitatory) neurons was sufficient to impair contextual fear memory, and snRNA-seq from these mice pointed to IL-4-driven regulation of synaptic function in promoting memory. These findings provide new insights into complex neuroimmune interactions at the transcriptional and functional levels in neurons under physiological conditions.

2.
Nature ; 596(7873): 486, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34429543
3.
Science ; 373(6554): 490-491, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34326223
4.
Science ; 373(6553)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34083450

RESUMO

The meninges contain adaptive immune cells that provide immunosurveillance of the central nervous system (CNS). These cells are thought to derive from the systemic circulation. Through single-cell analyses, confocal imaging, bone marrow chimeras, and parabiosis experiments, we show that meningeal B cells derive locally from the calvaria, which harbors a bone marrow niche for hematopoiesis. B cells reach the meninges from the calvaria through specialized vascular connections. This calvarial-meningeal path of B cell development may provide the CNS with a constant supply of B cells educated by CNS antigens. Conversely, we show that a subset of antigen-experienced B cells that populate the meninges in aging mice are blood-borne. These results identify a private source for meningeal B cells, which may help maintain immune privilege within the CNS.


Assuntos
Subpopulações de Linfócitos B/fisiologia , Linfócitos B/fisiologia , Células da Medula Óssea/fisiologia , Sistema Nervoso Central/imunologia , Dura-Máter/citologia , Linfopoese , Meninges/citologia , Meninges/imunologia , Crânio/anatomia & histologia , Envelhecimento , Animais , Subpopulações de Linfócitos B/imunologia , Movimento Celular , Sistema Nervoso Central/fisiologia , Dura-Máter/imunologia , Fibroblastos/fisiologia , Homeostase , Privilégio Imunológico , Camundongos , Plasmócitos/fisiologia , Análise de Célula Única
5.
Science ; 373(6553)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34083447

RESUMO

The meninges are a membranous structure enveloping the central nervous system (CNS) that host a rich repertoire of immune cells mediating CNS immune surveillance. Here, we report that the mouse meninges contain a pool of monocytes and neutrophils supplied not from the blood but by adjacent skull and vertebral bone marrow. Under pathological conditions, including spinal cord injury and neuroinflammation, CNS-infiltrating myeloid cells can originate from brain borders and display transcriptional signatures distinct from their blood-derived counterparts. Thus, CNS borders are populated by myeloid cells from adjacent bone marrow niches, strategically placed to supply innate immune cells under homeostatic and pathological conditions. These findings call for a reinterpretation of immune-cell infiltration into the CNS during injury and autoimmunity and may inform future therapeutic approaches that harness meningeal immune cells.


Assuntos
Células da Medula Óssea/fisiologia , Doenças do Sistema Nervoso Central/imunologia , Sistema Nervoso Central/imunologia , Meninges/imunologia , Células Mieloides/fisiologia , Crânio/anatomia & histologia , Coluna Vertebral/anatomia & histologia , Animais , Medula Óssea/fisiologia , Encéfalo/citologia , Encéfalo/imunologia , Encéfalo/fisiologia , Movimento Celular , Sistema Nervoso Central/citologia , Doenças do Sistema Nervoso Central/patologia , Dura-Máter/citologia , Dura-Máter/imunologia , Dura-Máter/fisiologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Homeostase , Meninges/citologia , Meninges/fisiologia , Camundongos , Monócitos/fisiologia , Neutrófilos/fisiologia , Medula Espinal/citologia , Medula Espinal/imunologia , Medula Espinal/fisiologia , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/patologia
6.
Circ Res ; 129(1): 174-194, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34166075

RESUMO

Appropriate vascular function is essential for the maintenance of central nervous system homeostasis and is achieved through virtue of the blood-brain barrier; a specialized structure consisting of endothelial, mural, and astrocytic interactions. While appropriate blood-brain barrier function is typically achieved, the central nervous system vasculature is not infallible and cerebrovascular anomalies, a collective terminology for diverse vascular lesions, are present in meningeal and cerebral vasculature supplying and draining the brain. These conditions, including aneurysmal formation and rupture, arteriovenous malformations, dural arteriovenous fistulas, and cerebral cavernous malformations, and their associated neurological sequelae, are typically managed with neurosurgical or pharmacological approaches. However, increasing evidence implicates interacting roles for inflammatory responses and disrupted central nervous system fluid flow with respect to vascular perturbations. Here, we discuss cerebrovascular anomalies from an immunologic angle and fluid flow perspective. We describe immune contributions, both common and distinct, to the formation and progression of diverse cerebrovascular anomalies. Next, we summarize how cerebrovascular anomalies precipitate diverse neurological sequelae, including seizures, hydrocephalus, and cognitive effects and possible contributions through the recently identified lymphatic and glymphatic systems. Finally, we speculate on and provide testable hypotheses for novel nonsurgical therapeutic approaches for alleviating neurological impairments arising from cerebrovascular anomalies, with a particular emphasis on the normalization of fluid flow and alleviation of inflammation through manipulations of the lymphatic and glymphatic central nervous system clearance pathways.

7.
Sci Adv ; 7(21)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34020948

RESUMO

Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)-dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer's disease-like brain ß-amyloid (Aß) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to reduced glymphatic influx and cognitive impairment. Deletion of CCR7 in 5xFAD transgenic mice resulted in deleterious neurovascular and microglial activation, along with increased Aß deposition in the brain. Treating old mice with anti-CD25 antibodies alleviated the exacerbated meningeal regulatory T cell response and improved cognitive function, highlighting the therapeutic potential of modulating meningeal immunity to fine-tune brain function in aging and in neurodegenerative diseases.

8.
Nature ; 593(7858): 255-260, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33911285

RESUMO

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.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Imunoterapia , Vasos Linfáticos/imunologia , Meninges/imunologia , Microglia/imunologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/imunologia , Doença de Alzheimer/genética , Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/efeitos dos fármacos , Animais , Anticorpos Monoclonais Humanizados/imunologia , Encéfalo/irrigação sanguínea , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Modelos Animais de Doenças , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Masculino , Meninges/irrigação sanguínea , Meninges/citologia , Camundongos , Microglia/citologia , Microglia/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Fator C de Crescimento do Endotélio Vascular/metabolismo , Fator C de Crescimento do Endotélio Vascular/farmacologia
9.
Nat Rev Immunol ; 21(8): 526-541, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33649606

RESUMO

Interactions between the immune system and the nervous system have been described mostly in the context of diseases. More recent studies have begun to reveal how certain immune cell-derived soluble effectors, the cytokines, can influence host behaviour even in the absence of infection. In this Review, we contemplate how the immune system shapes nervous system function and how it controls the manifestation of host behaviour. Interactions between these two highly complex systems are discussed here also in the context of evolution, as both may have evolved to maximize an organism's ability to respond to environmental threats in order to survive. We describe how the immune system relays information to the nervous system and how cytokine signalling occurs in neurons. We also speculate on how the brain may be hardwired to receive and process information from the immune system. Finally, we propose a unified theory depicting a co-evolution of the immune system and host behaviour in response to the evolutionary pressure of pathogens.


Assuntos
Citocinas/imunologia , Citocinas/fisiologia , Sistema Imunitário/imunologia , Sistema Imunitário/fisiologia , Neuroimunomodulação/imunologia , Neuroimunomodulação/fisiologia , Animais , Comportamento Animal/fisiologia , Evolução Biológica , Encéfalo/imunologia , Encéfalo/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Comportamento de Doença/fisiologia , Infecções/imunologia , Infecções/fisiopatologia , Infecções/psicologia , Modelos Imunológicos , Modelos Neurológicos , Transdução de Sinais/imunologia , Transdução de Sinais/fisiologia
11.
Cell ; 184(4): 1000-1016.e27, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33508229

RESUMO

Despite the established dogma of central nervous system (CNS) immune privilege, neuroimmune interactions play an active role in diverse neurological disorders. However, the precise mechanisms underlying CNS immune surveillance remain elusive; particularly, the anatomical sites where peripheral adaptive immunity can sample CNS-derived antigens and the cellular and molecular mediators orchestrating this surveillance. Here, we demonstrate that CNS-derived antigens in the cerebrospinal fluid (CSF) accumulate around the dural sinuses, are captured by local antigen-presenting cells, and are presented to patrolling T cells. This surveillance is enabled by endothelial and mural cells forming the sinus stromal niche. T cell recognition of CSF-derived antigens at this site promoted tissue resident phenotypes and effector functions within the dural meninges. These findings highlight the critical role of dural sinuses as a neuroimmune interface, where brain antigens are surveyed under steady-state conditions, and shed light on age-related dysfunction and neuroinflammatory attack in animal models of multiple sclerosis.


Assuntos
Cavidades Cranianas/imunologia , Cavidades Cranianas/fisiologia , Dura-Máter/imunologia , Dura-Máter/fisiologia , Animais , Apresentação do Antígeno/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos/líquido cefalorraquidiano , Senescência Celular , Quimiocina CXCL12/farmacologia , Dura-Máter/irrigação sanguínea , Feminino , Homeostase , Humanos , Imunidade , Masculino , Camundongos Endogâmicos C57BL , Fenótipo , Células Estromais/citologia , Linfócitos T/citologia
12.
Nat Commun ; 11(1): 4524, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913280

RESUMO

Traumatic brain injury (TBI) is a leading global cause of death and disability. Here we demonstrate in an experimental mouse model of TBI that mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that begin within hours and last out to at least one month post-injury. To investigate a mechanism underlying impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics. We demonstrate that increased ICP can contribute to meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction before TBI leads to increased neuroinflammation and negative cognitive outcomes. Finally, we report that rejuvenation of meningeal lymphatic drainage function in aged mice can ameliorate TBI-induced gliosis. These findings provide insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.


Assuntos
Lesões Encefálicas/fisiopatologia , Gliose/fisiopatologia , Sistema Glinfático/fisiologia , Meninges/fisiopatologia , Animais , Lesões Encefálicas/complicações , Lesões Encefálicas/patologia , Lesões Encefálicas/terapia , Dependovirus/genética , Modelos Animais de Doenças , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Gliose/etiologia , Gliose/patologia , Gliose/prevenção & controle , Sistema Glinfático/patologia , Humanos , Masculino , Meninges/patologia , Camundongos , Fator C de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular/uso terapêutico
13.
Nat Immunol ; 21(11): 1421-1429, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32929273

RESUMO

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.


Assuntos
Ansiedade/etiologia , Ansiedade/metabolismo , Interleucina-17/metabolismo , Neurônios/imunologia , Neurônios/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Ansiedade/psicologia , Comportamento Animal , Proliferação de Células , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Modelos Animais de Doenças , Dura-Máter , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Interleucina-17/genética , Meninges/imunologia , Meninges/metabolismo , Camundongos , Camundongos Knockout , Receptores de Antígenos de Linfócitos T gama-delta/genética , Transdução de Sinais , Transcriptoma
14.
Cell ; 182(2): 270-296, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32707093

RESUMO

Mammals have two specialized vascular circulatory systems: the blood vasculature and the lymphatic vasculature. The lymphatic vasculature is a unidirectional conduit that returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays major roles in immune cell trafficking and lipid absorption. As we discuss in this review, the molecular characterization of lymphatic vascular development and our understanding of this vasculature's role in pathophysiological conditions has greatly improved in recent years, changing conventional views about the roles of the lymphatic vasculature in health and disease. Morphological or functional defects in the lymphatic vasculature have now been uncovered in several pathological conditions. We propose that subtle asymptomatic alterations in lymphatic vascular function could underlie the variability seen in the body's response to a wide range of human diseases.


Assuntos
Vasos Linfáticos/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , História do Século XXI , Humanos , Linfonodos/imunologia , Linfonodos/metabolismo , Linfangiogênese , Doenças Linfáticas/genética , Doenças Linfáticas/história , Doenças Linfáticas/patologia , Metástase Linfática , Vasos Linfáticos/anatomia & histologia , Vasos Linfáticos/citologia , Neoplasias/metabolismo , Neoplasias/patologia , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética
15.
Annu Rev Immunol ; 38: 597-620, 2020 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-32340575

RESUMO

Neuroimmunology, albeit a relatively established discipline, has recently sparked numerous exciting findings on microglia, the resident macrophages of the central nervous system (CNS). This review addresses meningeal immunity, a less-studied aspect of neuroimmune interactions. The meninges, a triple layer of membranes-the pia mater, arachnoid mater, and dura mater-surround the CNS, encompassing the cerebrospinal fluid produced by the choroid plexus epithelium. Unlike the adjacent brain parenchyma, the meninges contain a wide repertoire of immune cells. These constitute meningeal immunity, which is primarily concerned with immune surveillance of the CNS, and-according to recent evidence-also participates in postinjury CNS recovery, chronic neurodegenerative conditions, and even higher brain function. Meningeal immunity has recently come under the spotlight owing to the characterization of meningeal lymphatic vessels draining the CNS. Here, we review the current state of our understanding of meningeal immunity and its effects on healthy and diseased brains.


Assuntos
Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Suscetibilidade a Doenças , Homeostase , Imunidade , Meninges/fisiologia , Animais , Humanos , Vasos Linfáticos/imunologia , Vasos Linfáticos/metabolismo , Neuroimunomodulação , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
17.
J Immunol ; 204(2): 286-293, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31907271

RESUMO

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.


Assuntos
Encéfalo/imunologia , Vigilância Imunológica/imunologia , Vasos Linfáticos , Meninges/imunologia , Animais , Sistema Nervoso Central/imunologia , Humanos
19.
Cell Stem Cell ; 25(4): 449-451, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31585089

RESUMO

Neurogenesis is critical to continuously replacie olfactory neurons but is impaired during chronic inflammatory rhinosinusitis. In this issue of Cell Stem Cell, Chen et al. (2019) describe the inflammation-induced switching of olfactory stem cells from a regenerative phenotype to one participating in immune defense; this process contributes to deficient replacement of olfactory sensory neurons.


Assuntos
Regeneração Nervosa , Neurônios Receptores Olfatórios , Humanos , Inflamação , Neurogênese , Células-Tronco
20.
J Immunol ; 203(8): 2339-2350, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31519866

RESUMO

Unlike the blood, the interstitial fluid and the deriving lymph are directly bathing the cellular layer of each organ. As such, composition analysis of the lymphatic fluid can provide more precise biochemical and cellular information on an organ's health and be a valuable resource for biomarker discovery. In this study, we describe a protocol for cannulation of mouse and rat lymphatic collectors that is suitable for the following: the "omic" sampling of pre- and postnodal lymph, collected from different anatomical districts; the phenotyping of immune cells circulating between parenchymal organs and draining lymph nodes; injection of known amounts of molecules for quantitative immunological studies of nodal trafficking and/or clearance; and monitoring an organ's biochemical omic changes in pathological conditions. Our data indicate that probing the lymphatic fluid can provide an accurate snapshot of an organ's physiology/pathology, making it an ideal target for liquid biopsy.


Assuntos
Cateterismo , Linfonodos/imunologia , Linfa/imunologia , Vasos Linfáticos/imunologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley
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