Dwellers and Trespassers: Mononuclear Phagocytes at the Borders of the Central Nervous System

Abstract

The central nervous system (CNS) parenchyma is enclosed and protected by a multilayered system of cellular and acellular barriers, functionally separating glia and neurons from peripheral circulation and blood-borne immune cells. Populating these borders as dynamic observers, CNS-resident macrophages contribute to organ homeostasis. Upon autoimmune, traumatic or neurodegenerative inflammation, these phagocytes start playing additional roles as immune regulators contributing to disease evolution. At the same time, pathological CNS conditions drive the migration and recruitment of blood-borne monocyte-derived cells across distinct local gateways. This invasion process drastically increases border complexity and can lead to parenchymal infiltration of blood-borne phagocytes playing a direct role both in damage and in tissue repair. While recent studies and technical advancements have highlighted the extreme heterogeneity of these resident and CNS-invading cells, both the compartment-specific mechanism of invasion and the functional specification of intruding and resident cells remain unclear. This review illustrates the complexity of mononuclear phagocytes at CNS interfaces, indicating how further studies of CNS border dynamics are crucially needed to shed light on local and systemic regulation of CNS functions and dysfunctions.

The Glymphatic System (En)during Inflammation

“…In addition to altered AQP4 polarization, infiltrating immune cells are known to accumulate in the perivascular spaces during inflammation, and may then physically block perivascular flow and influx of CSF [ 18 , 91 , 92 ]. It is possible that the impairment of the glymphatic flow and resultant accumulation of cytokines [ 93 ] and metabolic wastes create a vicious cycle to perpetuate neuroinflammation (see Figure 2 ).…”

Central Nervous System Barriers Impact Distribution and Expression of iNOS and Arginase-1 in Infiltrating Macrophages During Neuroinflammation

“…Accumulation of MoCs at CNS borders is thus a key event in disease development (23,55). While the study of immune cell migration through distinct CNS access gateways has considerably increased the efficacy of MS treatments (56), research has however largely focused on lymphocyte dynamics (57-59), with the trafficking routes of circulating monocytes during neuroinflammation remaining surprisingly unclear (24). Furthermore, the anatomical sites and the mechanisms leading to the acquisition of pro-or anti-inflammatory specifications in CNS-invading MoCs have not been properly investigated.…”

“…Upon autoimmune inflammation, CNS interfaces become increasingly populated by tissue-invading MoCs (23,24), some of which display a complete functional polarization characterized by the expression of iNOS and/or arginase-1 (17). Whether M iNOS and M Arginase MoCs accumulate equally at different CNS gateways remains however unknown.…”

“…Leptomeningeal MoC accumulation can derive from local extravasation of monocytes through meningeal vessels or from CSF trafficking through the distal ChP (24). To visualize the density of MoCs at the ChP, we first made use of CX3CR1-GFP x CCR2-RFP mice, a model in which differential reporter expression allows distinction of infiltrating CCR2 + MoCs from long-lived CCR2 negative CX3CR1 high resident macrophages (9).…”

“…CCR2 + MoCs can accumulate in the ChP stroma following extravasation across local fenestrated capillaries and could subsequently cross the epithelial blood-CSF barrier to enter the CSF. However, no formal demonstration of this pathway exists in EAE and MS (24).…”