Cerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels

Mazzitelli, Jose A; Smyth, Leon; Cross, Kevin A; Dykstra, Taitea; Sun, Jerry; Du, Siling; Mamuladze, Tornike; Smirnov, Igor; Rustenhoven, Justin; Kipnis, Jonathan

doi:10.1038/s41593-022-01029-1

Cited by 124 publications

(115 citation statements)

References 26 publications

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“…At the crossroads of blood and immunity, bone marrow harbors a niche for hematopoietic cells and mature immune cells (Di Rosa and Pabst, 2005;Li et al, 2007;Melenhorst et al, 2009). In particular, skull and vertebral bone marrow have been reported to supply immune cells to meningeal borders and contribute to immune homeostasis in the CNS (Brioschi et al, 2021;Cugurra et al, 2021;Herisson et al, 2018;Mazzitelli et al, 2022). Indeed, we highlight the (A) Schematic diagram depicts experimental design.…”

Section: Discussionmentioning

confidence: 99%

“…As a central immune organ, bone marrow is the primary site of hematopoiesis that harbors hematopoietic stem and progenitor cells (HSPCs) to generate blood cells and to maintain immune homeostasis in the periphery and CNS (Brioschi et al, 2021;Cugurra et al, 2021;Herisson et al, 2018;Mazzitelli et al, 2022). Among various immune cell types from terminally differentiated progeny of HSPCs, those of the myeloid lineage predominate.…”

Section: Introductionmentioning

confidence: 99%

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Section: Discussionmentioning

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Section: Introductionmentioning

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Bone marrow hematopoiesis drives multiple sclerosis progression

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“…Bone marrow niches in the skull were shown to provide meninges with a continuous supply of myeloid cells through bone marrow–dura channels (Cugurra et al, 2021 ). Following this study, it was additionally shown proteins in the CSF provide cues for myelopoiesis and cell-trafficking to the meninges (Mazzitelli et al, 2022 ). Lymphatics in the meninges are also critical for brain immunosurveillance by T cells (Louveau et al, 2015 , 2018 ).…”

Section: Immunosurveillance and Brain Immune Homeostasismentioning

confidence: 73%

Changes in Brain Neuroimmunology Following Injury and Disease

Tabet

Apra

Stranahan

et al. 2022

Front. Integr. Neurosci.

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The nervous and immune systems are intimately related in the brain and in the periphery, where changes to one affect the other and vice-versa. Immune cells are responsible for sculpting and pruning neuronal synapses, and play key roles in neuro-development and neurological disease pathology. The immune composition of the brain is tightly regulated from the periphery through the blood-brain barrier (BBB), whose maintenance is driven to a significant extent by extracellular matrix (ECM) components. After a brain insult, the BBB can become disrupted and the composition of the ECM can change. These changes, and the resulting immune infiltration, can have detrimental effects on neurophysiology and are the hallmarks of several diseases. In this review, we discuss some processes that may occur after insult, and potential consequences to brain neuroimmunology and disease progression. We then highlight future research directions and opportunities for further tool development to probe the neuro-immune interface.

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“…As our hemiskull preparations include also skull bone marrow cells, we cannot exclude that a proportion of the measured cytokines derive from this niche. A recent paper demonstrated the presence of dural channels that provide direct access for the immune cells from skull bone marrow area to the meninges 72 : therefore, we cannot exclude that these skull bone marrow-derived immune cells play a role in the regulation of meningeal inflammation and nociception. This hypothesis and the role of meningeal lymphatics in the control of this trafficking need to be further elucidated.…”

Section: Discussionmentioning

confidence: 92%

The role of the meningeal lymphatic system in local meningeal inflammation and trigeminal nociception

Mikhailov

Virenque

Koroleva

et al. 2022

Sci Rep

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A system of lymphatic vessels has been recently characterized in the meninges, with a postulated role in ‘cleaning’ the brain via cerebral fluid drainage. As meninges are the origin site of migraine pain, we hypothesized that malfunctioning of the lymphatic system should affect the local trigeminal nociception. To test this hypothesis, we studied nociceptive and inflammatory mechanisms in the hemiskull preparations (containing the meninges) of K14-VEGFR3-Ig (K14) mice lacking the meningeal lymphatic system. We recorded the spiking activity of meningeal afferents and estimated the local mast cells population, calcitonin gene-related peptide (CGRP) and cytokine levels as well as the dural trigeminal innervation in freshly-isolated hemiskull preparations from K14-VEGFR3-Ig (K14) or wild type C57BL/6 mice (WT). Spiking activity data have been confirmed in an acquired model of meningeal lymphatic dysfunction (AAV-mVEGFR3(1–4)Ig induced lymphatic ablation). We found that levels of the pro-inflammatory cytokine IL12-p70 and CGRP, implicated in migraine, were reduced in the meninges of K14 mice, while the levels of the mast cell activator MCP-1 were increased. The other migraine-related pro-inflammatory cytokines (basal and stimulated), did not differ between the two genotypes. The patterns of trigeminal innervation in meninges remained unchanged and we did not observe alterations in basal or ATP-induced nociceptive firing in the meningeal afferents associated with meningeal lymphatic dysfunction. In summary, the lack of meningeal lymphatic system is associated with a new balance between pro- and anti-migraine mediators but does not directly trigger meningeal nociceptive state.

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Cerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels

Cited by 124 publications

References 26 publications

Bone marrow hematopoiesis drives multiple sclerosis progression

Bone marrow hematopoiesis drives multiple sclerosis progression

Changes in Brain Neuroimmunology Following Injury and Disease

The role of the meningeal lymphatic system in local meningeal inflammation and trigeminal nociception

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