Filiano, A. J. | bioRxiv Science

bioRxiv2026

Type-I IFNs in EAE drive synaptic transcriptional responses in neurons and astrocytes in the brain

Neuronal pathology plays a prominent role in the cognitive and neuropathic symptoms of multiple sclerosis; however, little is known about these pathological signals to neurons in the brain and their consequences on cognition. Here, using a transgenic reporter of IFN signaling with spatial RNA-sequencing, we determined myelin-specific autoimmune T cells enter the brain parenchyma through the interface between the fimbria and third ventricle. Here, astrocytes and microglia express high levels of MHC-II-associated transcripts. Using this reporter, we also showed microglia within the brain are not direct responders of IFNs, but express transcripts associated with synaptic pruning, potentially contributing to pathological remodeling of neuronal circuits. Moreover, both type-I and type-II IFNs are required for T cells to infiltrate the brain and initiate an IFN response associated with synaptic and metabolic programs in neurons and astrocytes in the cortex and hippocampus. In summary, this study elucidates multiple steps of the pathogenesis of EAE pathology within the brain independent of the spinal cord.

neuroscience↗

bioRxiv2019

Human Umbilical Cord blood monocytes, but not adult blood monocytes, rescue brain cells from hypoxic-ischemic injury: Mechanistic and therapeutic implications

Cord blood (CB) mononuclear cells (MNC) are being tested in clinical trials to treat hypoxic-ischemic (HI) brain injuries. Although early results are encouraging, mechanisms underlying potential clinical benefits are not well understood. To explore these mechanisms further, we exposed mouse brain organotypic slice cultures to oxygen and glucose deprivation (OGD) and then treated the brain slices with cells from CB or adult peripheral blood (PB). We found that CB-MNCs protect neurons from OGD-induced death and reduced both microglial and astrocyte activation. PB-MNC failed to affect either outcome. The protective activities were largely mediated by factors secreted by CB-MNC, as direct cell-to-cell contact between the injured brain slices and CB cells was not essential. To determine if a specific subpopulation of CB-MNC are responsible for these protective activities, we depleted CB-MNC of various cell types and found that only removal of CB CD14+ monocytes abolished neuroprotection. We also used positively selected subpopulations of CB-MNC and PB-MNC in this assay and demonstrated that purified CB-CD14+ cells, but not CB-PB CD14+ cells, efficiently protected neuronal cells from death and reduced glial activation following OGD. Gene expression microarray analysis demonstrated that compared to PB-CD14+ monocytes, CB-CD14+ monocytes over-expressed several secreted proteins with potential to protect neurons. Differential expression of five candidate effector molecules, chitinase 3-like protein-1, inhibin-A, interleukin-10, matrix metalloproteinase-9 and thrombospondin-1, were confirmed by western blotting, and immunofluorescence. These findings suggest that CD14+ monocytes are a critical cell-type when treating HI with CB-MNC.

neuroscience↗