Immune responses of the brain to endotoxemia-induced systemic inflammation in adult mice

Abstract

The brain is known to actively interact with the immune system under inflammatory conditions. However, acute immune reactions by intracranial tissues to endotoxemia-induced inflammation have not been clarified well. In the Pathology Research Team at the Faculty of Health Sciences of Kyorin University, we wanted to elucidate what intracranial tissues contribute to the initial responses, what cytokines are produced to spread inflammation to brain parenchyma, and how brain cells are activated to interact with systemic inflammation. The present article reviewed our previously published papers to go over our findings obtained with adult mouse experimental models. Two-month-old C57BL/6N mice were treated with single intraperitoneal injection of lipopolysaccharide (LPS) . Brains were removed at 4, 24, 48 and 72 h after LPS injection, and tissue concentrations of multiple cytokines were determined by immunoassays. The choroid plexuses were collected at 4 h after LPS. The brains were dissociated and CD11b (＋) cells were isolated at 48 h after LPS. RNA was extracted from these tissues and cells, and real-time RT-PCR was performed. For histology, mice were perfused with 4% paraformaldehyde at 1，4，24 and 48 h after LPS. The choroid plexus and leptomeninges responded at 1 h after LPS, evidenced by IL-1β production by macrophages. The choroid plexus epithelial and stromal cells then produced CCL2, CXCL1, CXCL2 and IL-6 at 4 h, which were transported into the brain parenchyma. Astrocytes responded most quickly among brain parenchymal cells using the cytokine receptors on the endfeet. Astrocytes thereafter produced CCL11, CXCL10 and G-CSF at 24 h after LPS. The cytokines derived from astrocytes activated microglia via receptors. Activated microglia changed gene expression pattern toward the M2 phenotype. The concentrations of brain cytokines returned to control levels by 72 h after LPS. Therefore, the choroid plexus and leptomeningeal macrophages responded most quickly to systemic inflammation and stimulated choroid plexus epithelial and stromal cells to produce CCL2, CXCL1, CXCL2 and IL-6. These cytokines stimulated astrocytes to produce CCL11, CXCL10 and G-CSF, which activated microglia to contribute to the resolution of neuroinflammation. This review was written as a report for the Intramural Grants Program “Health Sciences Collaborative Research Promotion Project”, in which the authors were awarded a grant in FY 2020.