AbstractBrain injury represents the leading cause of mortality and disability after cardiopulmonary resuscitation (CPR) from cardiac arrest (CA), in which the accumulation of dying cells aggravate tissue injury by releasing proinflammatory intracellular components. Microglia play an essential role in maintaining brain homeostasis via milk fat globule epidermal growth factor 8 (MFG‐E8)‐opsonized efferocytosis, the engulfment of dying cells and debris. This study investigates whether potentiating microglia efferocytosis by MFG‐E8 provides neuroprotection after CA/CPR. After 8‐minute asphyxial CA/CPR, male adult C57BL/6J mice were randomly assigned to receive recombinant mouse MFG‐E8 (rmMFG‐E8) or vehicle. We evaluated the survival and neurological deficits of mice, along with histological damages, phagocytosis index of dying cells, and microglia polarization. A transcriptome analysis was conducted to explore the downstream molecules modulated by MFG‐E8. In mice resuscitated from CA, rmMFG‐E8 administration significantly enhanced the efferocytosis of apoptotic cells by microglia, improved the survival and neurological function of mice, and attenuated neuropathological injuries. Additionally, rmMFG‐E8 induced a prominent alteration in microglial gene expression and promoted a shift from a proinflammatory phenotype to an anti‐inflammatory phenotype. Moreover, rmMFG‐E8 treatment induced up‐regulation of interferon regulatory factor 7 (IRF7), and IRF7 gene silencing largely reversed the neuroprotective effects of rmMFG‐E8. This study demonstrates that rmMFG‐E8 improves survival and neurological outcomes after CA/CPR by enhancing microglial efferocytosis and reshaping the inflammatory microenvironment in brain tissue. Potentiating MFG‐E8 is a promising strategy to combat post‐CA brain injury.

AbstractAmong the intrathecal inflammatory niches where compartmentalized inflammation persists and plays a pivotal role in progressive multiple sclerosis (MS), choroid plexus (CP) has recently received renewed attention. To better characterize the neuropathological/molecular correlates of CP in progressive MS and its potential link with other brain inflammatory compartments, such as perivascular spaces and leptomeninges, the levels, composition and phenotype of CP immune infiltration in lateral ventricles of the hippocampus were examined in 40 post‐mortem pathologically confirmed MS and 10 healthy donors, using immunochemistry/immunofluorescence and in‐situ sequencing. Significant inflammation was detected in the CP of 21 out of the 40 MS cases (52%). The degree of CP inflammation was found correlated with: number of CP macrophages (R: 0.878, p = 1.012 x 10‐13) and high frequency of innate immune cells expressing the markers MHC‐class II, CD163, CD209, CD11c, TREM2 and TSPO; perivascular inflammation (R: 0.509, p = 7.921 x 10‐4), and less with meningeal inflammation (R: 0.365, p = 0.021); number of active lesions (R: 0.51, p: 3.524 x 10‐5). However, it did not significantly correlate with any clinical/demographic characteristics of the examined population. In‐situ sequencing analysis of gene expression in the CP of 3 representative MS cases and 3 controls revealed regulation of inflammatory pathways mainly related to ‘type 2 immune response’, ‘defense to infections’, ‘antigen processing/presentation’. Analysis of 78 inflammatory molecules in paired post‐mortem CSF, the levels of fibrinogen (R: 0.640, p = 8.752 x 10‐6), PDGF‐bb (R: 0.470, p = 0.002), CXCL13 (R: 0.428, p = 0.006) and IL15 (R: 0.327, p = 0.040) were correlated with extent of CP inflammation. Elevated fibrinogen and complement deposition were found in CP and in underlying subependymal periventricular areas, according to “surface‐in” gradient associated with concomitant prominent microglia activation. CP inflammation, predominantly characterized by innate immunity, represents another key determinant of intrathecal, compartmentalised inflammation persisting in progressive MS, which may be possibly activated by fibrinogen and influence periventricular pathology, even without substantial association with clinical features.