Endotoxemia-induced cytokine-mediated responses of hippocampal astrocytes transmitted by cells of the brain–immune interface

Abstract

Systemic inflammation shifts the brain microenvironment towards a proinflammatory state. However, how peripheral inflammation mediates changes in the brain remains to be clarified. We aimed to identify hippocampal cells and cytokines that respond to endotoxemia. Mice were intraperitoneally injected with lipopolysaccharide (LPS) or saline, and examined 1, 4, and 24 h after injection. Tissue cytokine concentrations in the spleens and hippocampi were determined by multiplex assays. Another group of mice were studied immunohistologically. Fourteen cytokines showed an increased concentration in the spleen, and 10 showed an increase in the hippocampus after LPS injection. Cytokines increased at 4 h (CCL2, CXCL1, CXCL2, and interleukin-6) were expressed by leptomeningeal stromal cells, choroid plexus stromal cells, choroid plexus epithelial cells, and hippocampal vascular endothelial cells, all of which were located at the brain–immune interface. Receptors for these cytokines were expressed by astrocytic endfeet. Cytokines increased at 24 h (CCL11, CXCL10, and granulocyte-colony stimulating factor) were expressed by astrocytes. Cells of the brain–immune interface therefore respond to endotoxemia with cytokine signals earlier than hippocampal parenchymal cells. In the parenchyma, astrocytes play a key role in responding to signals by using endfeet located in close apposition to the interface cells via cytokine receptors.

Concurrent cell type–specific isolation and profiling of mouse brains in inflammation and Alzheimer’s disease

“…However, significant changes in some genes were confounded or absent due to their differential regulation in separate cell types, including Il6 and H2ab1, which were either significantly or trending upregulated in astrocytes and vascular endothelia but downregulated in microglia ( Figure 4 and Supplemental Table 2). Similar results were obtained by others when comparing the differential expressed genes of bulk brain (43) challenged with peripheral LPS to those of microglia (5,26,44) or astrocytes (5,13,44). These findings validate our system and emphasize the importance of cell type-specific analysis, as significant expression changes are masked when using whole brain.…”

Histological Architecture Underlying Brain–Immune Cell–Cell Interactions and the Cerebral Response to Systemic Inflammation

“…Therefore, immune cells can interact with brain parenchymal cells via at least four types of histological architecture. This figure is a modification of copyrighted material permitted by Nature Publishing Group (31), License Id: 3917450680042.…”

“…(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.…”

“…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. We then immunohistologically identified cells involved in the elevation of hippocampal cytokine levels (31). The concentration of at least 10 cytokines increases in the hippocampus in response to endotoxemia.…”

Environmental Toxicants-Induced Immune Responses in the Olfactory Mucosa

“…Poly(I:C) is a synthetic analog of viral double-stranded RNA, and is recognized by Toll-like receptor 3 (TLR3) (35), whereas LPS is an endotoxin found in the outer membrane of Gram-negative bacteria that activates another type of Toll-like receptor, TLR4 (36, 37). When injected intraperitoneally, LPS caused systemic inflammation that also changes the level of inflammatory cytokines in the brain (38). SG and RA are macrocyclic trichothecen mycotoxins produced by fungi such as Stachybotrys chartarum , the “black mold” (39).…”