Arachnoid granulations – How the Human Brain Drains Fluid

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New research at RUSH is changing current understanding of the brain by revealing new knowledge about structures involved in cleansing it of fluids and waste with a steady fluid stream.

Arachnoid granulations (AG) are poorly investigated. Historical reports suggest that they regulate brain volume by passively transporting cerebrospinal fluid (CSF) into dural venous sinuses. Here, we studied the microstructure of cerebral AG in humans with the aim of understanding their roles in physiology.

We discovered marked variations in AG size, lobation, location, content, and degree of surface encapsulation. High-resolution microscopy shows that AG consist of outer capsule and inner stromal core regions.

The fine and porous framework suggests uncharacterized functions of AG in mechanical CSF filtration. Moreover, internal cytokine and immune cell enrichment imply unexplored neuroimmune properties of these structures that localize to the brain–meningeal lymphatic interface. Dramatic age-associated changes in AG structure are additionally identified.

This study depicts for the first time microscopic networks of internal channels that communicate with perisinus spaces, suggesting that AG subserve important functions as transarachnoidal flow passageways.

These data raise new theories regarding glymphatic–lymphatic coupling and mechanisms of CSF antigen clearance, homeostasis, and diseases.

reference link : https://rupress.org/jem/article/220/2/e20220618/213737/Arachnoid-granulations-are-lymphatic-conduits-that

Arachnoid granulations (AG), which are also known as Pacchionian bodies, uniquely localize to the mammalian brain–dura interface and remain minimally investigated across species.

These central nervous system (CNS) structures were described as early as the 16th century and were called glandulae congoblatae by Pacchioni, who proposed that they are secretory bodies that have roles in CNS lubrication (Brunori et al., 1993; Pollay, 2010).

Conversely, Weed conjectured that AG house internal channels that facilitate egress of cerebrospinal fluid (CSF; Weed, 1914; Weed, 1917). Since these early classical works, AG have generally been regarded as the primary CSF outflow paths responsible for brain volume regulation in humans (Welch and Friedman, 1959; Welch and Friedman, 1960; Wolpow and Schaumburg, 1972).

Yet, the precise functions and structure of fluid pathways within AG have remained elusive, and the morphology, cytology, and anatomical relationships of AG have been a matter of debate over centuries, leaving unanswered questions regarding their biological significance at CNS interfaces.

Increasing data suggest that CSF circulation serves critical roles in brain maintenance (Louveau et al., 2015; Da Mesquita et al., 2018a; Mestre et al., 2020). Yet, specific mechanisms and pathways involved in CSF passage within intracranial cavities remain incompletely explained (Keep et al., 2019; Rustenhoven et al., 2021).

Historical literature asserts that AG protrude through dura, permitting CSF drainage into dural venous spaces (DVS, i.e., dural venous sinuses, dural veins, and lacunae; Kida et al., 1988; Kida et al., 1993; Welch and Pollay, 1961). Dura and arachnoid mater have been suggested to fuse focally on AG at DVS sites and, consequently, it has been concluded that AG and DVS lumina communicate (Gomez et al., 1974; Nabeshima et al., 1975).

However, direct evidence and precise mechanisms and pathways by which CSF is transported within and across AG have not been delineated, and investigation of this tissue is challenging in live humans. Microscopic endothelial-lined gaps, pores, and/or surface crypts have been represented on a few postmortem AG surfaces at DVS interfaces (Gomez et al., 1974; Kida et al., 1988).

Some researchers have speculated that internal endothelial-lined nonvascular tubules permit passive fluid flux across AG via open and direct communications (Gomez et al., 1974; Welch and Friedman, 1960; Upton and Weller, 1985), though others purport that AG fluid transmits into DVS via transcellular movement (Kida et al., 1988; Kida et al., 1993; Tripathi, 1977; Weller et al., 2018). To date, the delicate histology of AG has yet to be fully elucidated.

Given the paucity of studies on AG anatomy combined with the lack of systematically acquired histologic evidence in published reports (Jayatilaka., 1965a; Jayatilaka., 1965b; Weller et al., 2018), we here systematically analyzed the anatomy of human AG using a panel of cellular and molecular markers.

We show that human AG are comprised of a central collagen framework that is variably encapsulated and only a subset associate with DVS tissues. We also demonstrate that internal collagen forms a stromal meshwork and definitively depict for the first time immune cell enrichment within AG cores. Furthermore, we illustrate that AG domes border nonsinus spaces.

Given published in vivo tracer evidence and data presented here, it is inferred that AG fluid permeates freely into perisinus and diploic compartments, and we conclude that AG serve as CSF reservoirs and immune hubs at meningeal interfaces.

This study also characterizes prominent age-associated degenerative changes, which may be due to fluid stasis and likely account for anatomic discrepancies in prior reports. In light of recent insights regarding intracerebral fluid movement and the existence of meningeal lymphatic channels in mammalian species (Absinta et al., 2017; Louveau et al., 2015; Da Mesquita et al., 2018a) this work provides a novel conceptual framework for understanding and investigating glymphatic–lymphatic flow and brain antigen processing in mammals and may provide new clues into the neurophysiology and pathogenesis of a range of diseases.

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