A schematic representation of CNS compartmentalization highlights the formation of specific innate immune cell niches. The skull marrow contains hematopoietic stem cells (HSCs), thereby providing innate immune cells, including monocytes and macrophages, to the dura mater through vascularized bony channels. The cerebrospinal fluid (CSF) accesses the dura mater via gaps in the arachnoid barrier cell layer near bridging veins, drains into lymphatic vessels, and can also reach the skull marrow. Dural macrophages (M) are associated with dural sinuses and lymphatic vessels but are also distributed interstitially. The blood vessel network in the dura mater contains fenestrated endothelial cells, which allow the leakage of larger molecules into the dura. The arachnoid barrier cell layer, with its tight junctions, confines the CSF-filled subarachnoid space, which harbors leptomeningeal macrophages. Blood vessels within this space are ensheathed by pial perivascular fibroblasts, which extend into the brain parenchyma, following orthogonally entering blood vessels. This creates the CSF-filled perivascular space, defined by the vascular basement membrane on one side and the parenchymal basement membrane and astrocytic endfeet on the other. At the capillary level, the vascular and parenchymal basement membranes merge into a single layer, eliminating any visible perivascular space. Within these spaces, perivascular macrophages (pvM) are the predominant immune cells. Microglia, by contrast, are the sole immune cells present in the CNS parenchyma. CAMs, CNS-associated macrophages.
