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Although macrophages in the meningeal compartments of the central nervous system (CNS) have been comprehensively characterized under steady state, studying their contribution to physiological and pathological processes has been hindered by the lack of specific targeting tools in vivo. Recent findings have shown that the dural sinus and its adjacent lymphatic vessels act as a neuroimmune interface. However, the cellular and functional heterogeneity of extrasinusoidal dural macrophages outside this immune hub is not fully understood. Therefore, we comprehensively characterized these cells using single-cell transcriptomics, fate mapping, confocal imaging, clonal analysis, and transgenic mouse lines. Extrasinusoidal dural macrophages were distinct from leptomeningeal and CNS parenchymal macrophages in terms of their origin, expansion kinetics, and transcriptional profiles. During autoimmune neuroinflammation, extrasinusoidal dural macrophages performed efferocytosis of apoptotic granulocytes. Our results highlight a previously unappreciated myeloid cell diversity and provide insights into the brain's innate immune system. Editor's summary: The dura mater is the outermost layer of the meninges that protects the brain and spinal cord. Dural macrophages contribute to central nervous system (CNS) homeostasis and immune responses, but macrophages residing outside the sinusoidal regions remain poorly understood. Using single-cell transcriptomics, fate mapping, and confocal imaging, Amann et al. characterized extrasinusoidal macrophages in the murine dura mater. During homeostasis, extrasinusoidal dural macrophages were continuously replaced by monocytes and underwent clonal expansion. During experimental autoimmune encephalitis, extrasinusoidal dural macrophages exhibited increased turnover and were responsible for removing dying neutrophils. These findings demonstrate that extrasinusoidal dural macrophages represent a distinct subset of CNS-associated macrophages whose function is shaped by autoimmune neuroinflammation. —Claire Olingy [ABSTRACT FROM AUTHOR]

Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we summarize the state of the field and point out the gaps of knowledge that should be filled through further research. We discuss the glymphatic system as a system that allows CNS perfusion by the cerebrospinal fluid (CSF) and interstitial fluid (ISF). We also describe the recently characterized meningeal lymphatic vessels and their role in drainage of the brain ISF, CSF, CNS-derived molecules, and immune cells from the CNS and meninges to the peripheral (CNS-draining) lymph nodes. We speculate on the relationship between the two systems and their malfunction that may underlie some neurological diseases. Although much remains to be investigated, these new discoveries have changed our understanding of mechanisms underlying CNS immune privilege and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems., Perivascular pathways: pseudolymphatic vessels of the brain? In peripheral organs, colloids are extravasated across a fenestrated capillary bed, and these proteins, as well as excess tissue fluid, are returned to [...]

The central nervous system undergoes constant immune surveillance, but the route that immune cells take to exit the brain has been unclear as it had been thought to lack a classical lymphatic drainage system; here functional lymphatic vessels able to carry both fluid and immune cells from the cerebrospinal fluid are shown to be located in the brain meninges. A lymphatic system for the brain The central nervous system is under constant immune surveillance, but the exit route for immune cells has been unclear as the brain was thought to lack a classical lymphatic drainage system. Jonathan Kipnis and colleagues now show that the brain does indeed possess functional lymphatic vessels, located in the meninges, and that these vessels are able to carry both fluid and immune cells from the cerebrospinal fluid. The presence of a classical lymphatic system in the central nervous system suggests that current thinking on brain tolerance and the immune privilege of the brain should be revisited. Malfunction of the meningeal lymphatic vessels could be a root cause of a variety of neuroimmunological disorders. One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment.sup.1,2,3, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood.sup.4,5,6. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction., Author(s): Antoine Louveau [sup.1] [sup.2] , Igor Smirnov [sup.1] [sup.2] , Timothy J. Keyes [sup.1] [sup.2] , Jacob D. Eccles [sup.3] [sup.4] [sup.5] , Sherin J. Rouhani [sup.3] [sup.4] [sup.6] [...]

Summary: The central nervous system (CNS) has been viewed as an immunologically privileged site, but emerging works are uncovering a large array of neuroimmune interactions primarily occurring at its borders. CNS barriers sites host diverse population of both innate and adaptive immune cells capable of, directly and indirectly, influence the function of the residing cells of the brain parenchyma. These structures are only starting to reveal their role in controlling brain function under normal and pathological conditions and represent an underexplored therapeutic target for the treatment of brain disorders. This review will highlight the development of the CNS barriers to host neuro‐immune interactions and emphasize their newly described roles in neurodevelopmental, neurological, and neurodegenerative disorders, particularly for the meninges. [ABSTRACT FROM AUTHOR]

Author(s): Antoine Louveau; Igor Smirnov; Timothy J. Keyes; Jacob D. Eccles; Sherin J. Rouhani; J. David Peske; Noel C. Derecki; David Castle; James W. Mandell; Kevin S. Lee; Tajie H. [...]

Change history: In this Article, Extended Data Fig. 9 was appearing as Fig. 2 in the HTML, and in Fig. 2, the panel labels 'n' and 'o' overlapped the figure; these errors have been corrected online., Author(s): Sandro Da Mesquita [sup.1] [sup.2] , Antoine Louveau [sup.1] [sup.2] , Andrea Vaccari [sup.3] [sup.4] , Igor Smirnov [sup.1] [sup.2] , R. Chase Cornelison [sup.4] , Kathryn M. Kingsmore [...]

The central nervous system was long thought to be an immune‐privileged organ, notably because of its lack of conventional lymphatic drainage. Years of scientific observations and the recent (re)discovery of the meningeal lymphatic system has brought new insights into the relationship of the brain with the peripheral immune system. The extended meningeal lymphatic network has been shown to be a major route for the circulation of molecular and cellular cerebrospinal fluid constituents to the cervical lymph nodes, and participates in the maintenance of brain function and the development of neurological disorders. In this review, we discuss the functional anatomy of the meningeal lymphatic network, its role in neuro‐inflammatory and neurodegenerative disorders, and its therapeutic potential. [ABSTRACT FROM AUTHOR]

The immunoreceptor-associated protein CD3ξ is known for its role in immunity and has also been implicated in neuronal development and synaptic plasticity. However, the mechanism by which CD3ξ regulates synaptic transmission remains unclear. In this study, we showed that mice lacking CD3ξ exhibited defects in spatial learning and memory as examined by the Barnes maze and object location memory tasks. Given that peripheral T cells have been shown to support cognitive functions and neural plasticity, we generated CD3ξ-/- mice in which the peripheral T cells were repopulated to a normal level by syngeneic bone marrow transplantation. Using this approach, we showed that T-cell replenishment in CD3ξ-/- mice did not restore spatial memory defects, suggesting that the cognitive deficits in CD3ξ-/- mice were most likely mediated through a T-cell-independent mechanism. In support of this idea, we showed that CD3ξ proteins were localized to glutamatergic postsynaptic sites, where they interacted with the NMDAR subunit GluN2A. Loss of CD3ξ in brain decreased GluN2A-PSD95 association and GluN2A synaptic localization. This effect was accompanied by a reduced interaction of GluN2A with the key NMDAR downstream signaling protein calcium/calmodulin-dependent protein kinase II (CaMKII). Using the glycine-induced, NMDA-dependent form of chemical long-term potentiation (LTP) in cultured cortical neurons, we showed that CD3ξ was required for activity-dependent CaMKII autophosphorylation and for the synaptic recruitment of the AMPAR subunit GluA1. Together, these results support the model that the procognitive function ofCD3ξ maybe mediated through its involvement in theNMDAR downstream signaling pathway leading to CaMKII-dependent LTP induction. [ABSTRACT FROM AUTHOR]

The recent (re)discovery of the meningeal lymphatic system has opened new theories as to how immune cells traffic and interact with the central nervous system (CNS). While evidence is accumulating on the contribution of the meningeal lymphatic system in both homeostatic and disease conditions, a lot remains unknown about the mechanisms that allow for interaction between the meningeal lymphatic system and immune cells. In this review, we synthesize the knowledge about the lymphatic immune interaction in the CNS and highlight the important questions that remain to be answered. [ABSTRACT FROM AUTHOR]