島田 厚良

Preterm birth is a serious public health problem worldwide. High survival rate is accompanied by relatively high incidence of long-term neurological disability. The neuropathological substrate of this disability in preterm infants consists of injuries of the cerebral white matter and gray matter. Bacterial infection is a key trigger of inflammatory pathways that damage the preterm brain, even without direct bacterial brain invasion. We recently revealed the mechanisms underlying the involvement of intracranial tissues and cells in early immune responses to acute systemic inflammation in postnatal mice. Lipopolysaccharide (LPS) was administered with a single intraperitoneal injection into postnatal day (P) 7 mice. Four hours later, the leptomeningeal macrophages initiated an intracranial reaction by producing IL-1β, which set the stage for the arachnoid, pial, and perivascular fibroblasts to act. These brain fibroblasts produced CCL2, which increased the number of brain parenchymal macrophages/microglia and led to their hypertrophy. The macrophages/microglia isolated from the brains of mice with systemic inflammation showed marked transcript expression of genes including Saa3, Irg1, Lcn2, and Cxcl9. The expression level of Saa3 reached its peak 4 and 12 hours after LPS administration. Saa3 expression was upregulated in the macrophages in the leptomeninges, choroid plexus stroma, perivascular space, and cerebellar medulla, as well as in the fibroblasts of the leptomeninges, choroid plexus stroma, and perivascular space. The leptomeningeal macrophages expressing Saa3 continued their developmental migration from the leptomeninges to the brain parenchyma. The blood-brain barrier of pups remained intact up to 72 hours after LPS administration at P7. The expression levels of Irg1, Lcn2, and Cxcl9 peaked 4 and 12 hours after LPS administration. The cells that prominently expressed Irg1, Lcn2, and Cxcl9 were the leptomeningeal macrophages, perivascular fibroblasts and choroid plexus epithelial cells, and leptomeningeal fibroblasts, respectively. The early enhancement of Saa3 expression played a key role in priming inflammation initiated by macrophages and fibroblasts. Early enhancement of Irg1 expression was crucial for determining the direction of the inflammatory response. The increase of Lcn2 was vital, sequestering the iron siderophore to limit bacterial growth. It was interesting to observe how the early immune responses to systemic inflammation in the postnatal mouse brain were initiated by migrating macrophages and leptomeningeal fibroblasts, leading to immediate gene upregulation to protect immature brain tissue. DOI https://doi.org/10.1186/s12974-025-03559-4

My goal is to understand how various cells of the choroid plexus exert immune-like reactions in response to systemic inflammation to change brain microenvironment via brain-immune cell-cell interaction.