Abstract
Although the brain is now known to actively interact with the immune system under non-inflammatory conditions, the site of cell–cell interactions between brain parenchymal cells and immune cells has been an open question until recently. Studies by our and other groups have indicated that brain structures such as the leptomeninges, choroid plexus stroma and epithelium, attachments of choroid plexus, vascular endothelial cells, cells of the perivascular space, circumventricular organs, and astrocytic endfeet construct the histological architecture that provides a location for intercellular interactions between bone marrow-derived myeloid lineage cells and brain parenchymal cells under non-inflammatory conditions. This architecture also functions as the interface between the brain and the immune system, through which systemic inflammation-induced molecular events can be relayed to the brain parenchyma at early stages of systemic inflammation during which the blood–brain barrier is relatively preserved. Although brain microglia are well known to be activated by systemic inflammation, the mechanism by which systemic inflammatory challenge and microglial activation are connected has not been well documented. Perturbed brain–immune interaction underlies a wide variety of neurological and psychiatric disorders including ischemic brain injury, status epilepticus, repeated social defeat, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Proinflammatory status associated with cytokine imbalance is involved in autism spectrum disorders, schizophrenia, and depression. In this article, we propose a mechanism connecting systemic inflammation, brain–immune interface cells, and brain parenchymal cells and discuss the relevance of basic studies of the mechanism to neurological disorders with a special emphasis on sepsis-associated encephalopathy and preterm brain injury.
Highlights
The central nervous system (CNS) used to be regarded as an immune-privileged organ [1]
In our second set of experiments described in the present article that has been originally published in Ref. [31], we induced endotoxemia by a single i.p. injection of LPS at a dose of 3 mg/ kg into mice, and by using Luminex multiplex assay technology, we identified cytokines that showed a change in concentration in the hippocampus and spleen
The leptomeninges, choroid plexus stroma and epithelium, attachments of choroid plexus, perivascular space, Circumventricular Organs (CVOs), and astrocytic endfeet construct the histological architecture that provides a location for intercellular interaction between bone marrow-derived myeloid lineage cells and brain parenchymal cells under non-inflammatory conditions or at early stages of systemic inflammation during which the blood–brain barrier (BBB) is relatively preserved and the brain parenchyma exhibit no necrotic tissue damage
Summary
The central nervous system (CNS) used to be regarded as an immune-privileged organ [1]. Bone marrow-derived cells that are in the process of lining up along the narrow channel of the attachments of choroid plexus may make cell–cell contact with astrocytic processes that express CX3CL1, resulting in their trafficking into brain parenchyma. In response to systemic inflammation induced by intraperitoneal injection of lipopolysaccharide (LPS), hippocampal vascular endothelial cells, leptomeningeal stromal cells, choroid plexus stromal cells, and choroid plexus epithelial cells produce early cytokines (such as CCL2, CXCL1, CXCL2, and IL-6) at 4 h after LPS injection (red arrows) The receptors for these cytokines are expressed by astrocytic endfeet that are localized in close apposition to vascular endothelial cells and leptomeningeal cells. The mechanism that connects systemic inflammation and microglial activation in preterm brains would be an especially promising avenue of research
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