Cerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels, 2022, Mazzitelli et al

[SNT Gatchaman]

Cerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels
Jose A. Mazzitelli, Leon C. D. Smyth, Kevin A. Cross, Taitea Dykstra,
Jerry Sun, Siling Du, Tornike Mamuladze, Igor Smirnov, Justin Rustenhoven and Jonathan Kipnis

It remains unclear how immune cells from skull bone marrow niches are recruited to the meninges. Here we report that cerebrospinal fluid (CSF) accesses skull bone marrow via dura-skull channels, and CSF proteins signal onto diverse cell types within the niches. After spinal cord injury, CSF-borne cues promote myelopoiesis and egress of myeloid cells into meninges.

This reveals a mechanism of CNS-to-bone-marrow communication via CSF that regulates CNS immune responses.

Link | PDF (PubMed/Nature)

 

[SNT Gatchaman]

We hypothesized that local CNS cues, contained in CSF, could instruct myeloid cell recruitment to the meninges. Efflux of molecules from the brain is achieved via the blood–brain barrier and via CSF perfusion through the brain in a process termed ‘glymphatic clearance’. Through a glymphatic mechanism, brain-derived molecules are continuously cleared via CSF, efflux to the parasagittal dura mater and subsequently drain through meningeal lymphatic vessels, enabling immune surveillance of the CNS from distant sites.

Recent studies demonstrated that skull bone marrow also connects directly to the underlying dura through ossified vascular channels. Although these channels have been previously described to allow myeloid and lymphoid cell migration from the skull bone marrow to the dura, we speculated that these pathways might be bi-directional, allowing bone marrow direct access to the CSF. Here we show that CSF accesses skull bone marrow niches, where it regulates myelopoiesis and egress to meninges in physiology and pathology.

Understanding of the mechanisms regulating meningeal immune supply is evolving. In this study, we describe a previously unrecognized form of neuroimmune communication between the CNS and its surrounding immune reservoirs.

Additionally, we show that skull bone marrow populations have a unique transcriptional identity compared to non-CNS-associated bone marrow, suggesting that CSF-derived factors might instruct the phenotype of skull bone marrow populations. Indeed, access of brain-derived antigens along with CSF to skull bone marrow may underlie central tolerance of B cells educated in this niche.

Understanding how changes in CSF composition affect local immune supply from bone marrow niches will shed light on pathogenic mechanisms contributing to neurodevelopmental disorders, neurodegeneration, autoimmunity and CNS cancers.