The segregation and limited regenerative capacity of the CNS necessitate a specialized and tightly regulated resident immune system that continuously guards the CNS against invading pathogens and injury. Immunity in the CNS has generally been attributed to neuron-associated microglia in the parenchyma, whose origin and functions have recently been elucidated. However, there are several other specialized macrophage populations at the CNS borders, including dural, leptomeningeal, perivascular and choroid plexus macrophages (collectively known as CNS-associated macrophages (CAMs)), whose origins and roles in health and disease have remained largely uncharted. CAMs are thought to be involved in regulating the fine balance between the proper segregation of the CNS, on the one hand, and the essential exchange between the CNS parenchyma and the periphery, on the other. Recent studies that have been empowered by major technological advances have shed new light on these cells and suggest central roles for CAMs in CNS physiology and in the pathogenesis of diseases.
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The authors apologize to all those colleagues whose work was discussed without proper citation, owing to space constraints. The authors thank C. Gross and A.G. Peres for excellent help in editing the review. This study was supported by the German Research Foundation (DFG) under Germany’s Excellence Strategy (CIBSS EXC-2189, Project ID 390939984). M.P. is supported by the BMBF (Federal Ministry of Education and Research)-funded competence network of multiple sclerosis (KKNMS), the Sobek Foundation, the Ernst-Jung Foundation, the DFG (SFB 992, SFB1160, SFB/TRR167, Reinhart-Koselleck-Grant) and the Ministry of Science, Research and Arts, Baden-Wuerttemberg (Sonderlinie “Neuroinflammation”).
The authors declare no competing interests.
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The self-renewing population of tissue macrophages in the CNS parenchyma, which serve a plethora of functions during development and homeostasis and are implicated in many neurodegenerative and neuroimmunological diseases of the CNS.
- Lymphatic system
A vasculature system throughout the body that consists of low-pressure vessels that drain interstitial fluid from all organs to the heart and also serve important immune functions by allowing immune cell trafficking between organs, the lymph nodes and the spleen.
- Immune surveillance
The constant patrol of circulating and resident immune cells throughout the body and within their host tissue. The cells recognize and eliminate invading pathogens, clean up tissue injuries and remove unwanted host cells, such as cancer cells.
- Antigen presentation
An essential immune process in which antigen-presenting cells (such as dendritic cells) trigger adaptive T cell responses against specific antigens by presenting antigen epitopes and co-stimulatory signals on their surface.
- Yolk sac
A membranous sac present in most developing vertebrate embryos, which provides the embryo with nutrients by a direct connection via blood vessels and also harbours the blood islands, the specialized region within which the first haematopoietic cells of the embryo arise.
- Clonal expansion
The extensive proliferation of a group of identical cells that are originally derived from the same ancestor cell.
- Blood–brain barrier
(BBB). A multicellular barrier system that separates the CNS parenchyma from the periphery along CNS interfaces and restricts immune cell migration to the CNS.
- Single-cell RNA sequencing
(scRNA-seq). A new, unbiased technology using next-generation sequencing to evaluate the gene expression profile of single cells within a whole tissue or an isolated group of cells.
Activation of astrocytes by inflammation, injury or an infection, characterized by extensive proliferation, morphological changes and cytokine secretion.
- T helper cells
Specialized CD4+ T cells that are involved in the adaptive immune response. T helper cells are activated and expand upon antigen presentation. They secrete important cytokines to support the immune response of macrophages, B cells and also cytotoxic T cells.
- Dendritic cells
Professional antigen-presenting cells of the innate immune system that constantly digest and process antigens and present them to T cells to induce an antigen-specific adaptive immune response.
- Induced pluripotent stem cells
An artificially generated type of pluripotent stem cell, produced by the reprogramming of adult differentiated cells with defined factors ex vivo.
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Kierdorf, K., Masuda, T., Jordão, M.J.C. et al. Macrophages at CNS interfaces: ontogeny and function in health and disease. Nat Rev Neurosci 20, 547–562 (2019). https://doi.org/10.1038/s41583-019-0201-x
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