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Review
. 2024 Apr 29;25(9):4865.
doi: 10.3390/ijms25094865.

CNS Resident Innate Immune Cells: Guardians of CNS Homeostasis

Luca Muzio  1 , Jessica Perego  1
Affiliations
Review

CNS Resident Innate Immune Cells: Guardians of CNS Homeostasis

Luca Muzio et al. Int J Mol Sci. .

Abstract

Although the CNS has been considered for a long time an immune-privileged organ, it is now well known that both the parenchyma and non-parenchymal tissue (meninges, perivascular space, and choroid plexus) are richly populated in resident immune cells. The advent of more powerful tools for multiplex immunophenotyping, such as single-cell RNA sequencing technique and upscale multiparametric flow and mass spectrometry, helped in discriminating between resident and infiltrating cells and, above all, the different spectrum of phenotypes distinguishing border-associated macrophages. Here, we focus our attention on resident innate immune players and their primary role in both CNS homeostasis and pathological neuroinflammation and neurodegeneration, two key interconnected aspects of the immunopathology of multiple sclerosis.

Keywords: MS; brain tissue macrophages; innate immune cells; meningeal immunity.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The CNS innate immune system during homeostasis. Scheme of the innate immune populations of the brain under physiological conditions, divided by anatomical areas. Brain parenchyma: under physiological conditions, microglia are highly abundant in the CNS. Resting microglia cell morphology features a small cell body with a highly branched ramified morphology. Key phenotypic markers are TMEM119, SALL1, CX3CR1, P2Y12, MerTK, and Iba1. CNS meninges: The meninges are membranes surrounding the brain and the spinal cord: the dura mater, the arachnoid mater, and the pia mater. The arachnoid and pia mater delimit the subarachnoid space and are collectively defined as leptomeninges. BAMs, dendritic cells, and ILCs populate the meninges of the healthy brain. BAMs can be distinguished in subdural (MHC-II low, Egfl7+, and Lyve1+) and dural macrophages (both MHC-II high and low). NKs, ILC1, heterogeneous LTi/LTi-like cells, and NCR+ ILC3s have been found in all three meningeal layers, while ILC2s populate mainly the dura mater but are absent in the leptomeninges. Choroid plexus: The primary function of the choroid plexus is the secretion and modulation of CSF. CpMΦ (ApoE+, Ms4a7+, and Ms4a6c76+) are the largest class of innate immune cells in the choroid plexus and are predominantly associated with blood vessels. Dendritic cells are present in the choroid plexus and in the CSF. NKs and ILC1 have been found in the choroid plexus but in smaller amounts compared with the meninges, while ILC3 is absent and ILC2 abundance increases in an age-dependent way. Perivascular spaces are populated mainly by dendritic cells and PvMΦ (CD163+, CD206+, and Lyve1+). PvMΦ is located between the vascular basement membrane and the glial limitans of the brain parenchyma and is part of the neurovascular unit (NVU), composed of non-fenestrated endothelial cells, pericytes, and astrocyte endfeet.
Figure 2
Figure 2
Involvement of CNS resident innate immune cells in neuroinflammation. CNS resident innate immune cells can both boost and fight against neuroinflammation. The left side of the image represents their pro-inflammatory potential (1–5), while on the right side, it is depicted as their anti-inflammatory role (6–8). Left side: (1) Microglia and meningeal macrophages recruit peripheral inflammatory cells into the CNS. (2) ILC1s in the choroid plexus favor the entry of peripheral inflammatory cells through the expression of IFN-γ and TNF-α. (3) Microglia, BAMs, and resident cDCs foster T-cell activation through overexpression of MHC-II and co-stimulatory molecules. (4) ILC3s act as APCs to autoimmune T cells in focal lesions of the CNS parenchyma. Furthermore, accumulated ILC3s release pro-inflammatory cytokines such as IFN-γ, IL-17, and GM-CSF, which boost chronic inflammation. (5) NK and ILC1 favor the recruitment of inflammatory Th17. Right side: (6) Microglia can phagocytose and kill CNS-infiltrating Th17 cells, counteracting inflammation. (7) After the disease onset, cDCs prime the development of regulatory T cells instead of Th17. (8) ILC2 switch the differentiation of CD4+ T cells into Th2, at the expense of Th17 activation.
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