MFGE8 Improved Brain Functional Connectivity Between CA1 and LEnt by Activating Efferocytosis in Hippocampus of SAE Rats

Abstract Background: Sepsis-associated encephalopathy (SAE) is one of the most serious complications of sepsis, along with brain function and cognitive behavioral changes. The process of efferocytosis with microglia was restrained in SAE rats’ hippocampus. We have previously shown that milk fat globule EGF factor 8 protein (MFG-E8) evoked efferocytosis in SAE rats’ brain, and alleviated the inflammnation in hippocampus. The present study investigated the the contribution of MFG-E8 to the brain functional connectivity (FC) of hippocampus and lateral entorhinal cortex in SAE rats by resting-state functional MRI scan.Methods: Sixty adult male Sprague Dawley rats were divided randomly into Sham operation group, cecal ligation and puncture (CLP) group, CLP+MFGE8 group, and CLP+MFGE8+Cilengitide group. After cecal ligation and puncture (CLP) surgery, MFGE8 (3.3ug) was injected intracerebroventricularly (i.c.v.) and cilengitide (10 mg/kg) was injected intraperitoneal. The Morris water maze (MWM) and open filed test (OFT) were performed continuously for five days. Rats were detected by T2-MRI and rs-fMRI scan 8 days post-surgery, then brain tissues were taken for western blotting and pathological observation by HE stained. One-way ANOVA with Tukey’s post-test of all pair of columns was employed statistical analyses.Results: MFGE8 improved performance of neurobehavioral tests in MWM test and OFT. Expression of IL-1β and the proteins of MFGE8, Rac1, and LC3 were up regulated in CLP+MFGE8 group. On the contrary, expression of IL-6, Rac1, and LC3 were down regulated in CLP+MFGE8+cilengitide group. MFGE8 significantly decreased the hyperintense region in hippocampus detected by T2-MRI, and increased ALFF value in SAE rats’ bilateral sensory cortex, motor cortex and visual cortex by rs-fMRI. In addition, MFGE8 increased FC of CA1 and LEnt in same side of cerebral hemisphere, and the FC of CA1 and LEnt was consistent with the behavior result in Morris water maze test.Conclusions: MFGE8 activated efferocytosis with microglia and improved brain function and functional connectivity between CA1 and LEnt which were reflected in behavior tests and fMRI.