MFGE8/Integrin β3 pathway alleviates apoptosis and inflammation in early brain injury after subarachnoid hemorrhage in rats

Abstract

Background Milk fat globule-epidermal growth factor-factor 8(MFGE8)/Integrin β3 pathway was reported to be involved in reducing oxidative stress and early brain injury after Subarachnoid Hemorrhage (SAH). In the present study, the potential effects of MFGE8 and its receptor Integrin β3 in the inhibition of apoptosis and neuroinflammation in early brain injury after SAH were investigated. Methods Ninety-five (95) male Sprague-Dawley rats were used. The SAH model was induced by endovascular perforation. Recombinant human MFGE8 (rhMFGE8), MFGE8 small interfering RNA (siRNA) and Integrin β3 siRNA were injected intracerebroventricularly. SAH grade, neurologic scores, Western blots and immunofluorescence were employed to study the mechanisms of MFGE8 and its receptor Integrin β3, as well as neurological outcome. Results SAH induced significant neuronal apoptosis and inflammation and exhibited neurological dysfunction in rats. Knockdown endogenous MFGE8 with siRNA significantly increased the protein levels of cleaved caspase 3 and IL-1β, accompanied with more neurological deficits. rhMFGE8 significantly reduced neural cell death in cortex, decreased cleaved caspase 3 and IL-1β expressions, and improved neurological functions 24 hours after SAH. The anti-apoptosis and anti-inflammation effects of rhMFGE8 were abolished by integrin-β3 siRNA. Conclusion MFGE8 could alleviate neurologic damage in early brain injury after SAH via anti-inflammation and anti-apoptosis effects. MFGE8 may serve as a promising therapeutic target for future management of SAH patients.

Endogenous neural stem cells modulate microglia and protect from demyelination

“…EGFR (epidermal growth factor receptor) and ASCL1 (achaete-scute homolog1) are indeed commonly used markers for C cells. MFGE8 (milk fat globule-epidermal growth factor-8) and its receptor β3 integrin (Itgb3) are known to induce phagocytosis of apoptotic cells and to act as "endogenous protective factors" in response to various brain lesions (Deroide et al 2013, Liu et al 2015, Xiao et al 2018. We found β3 Integrin expressed in most of the microglial cells present in the demyelinated CC (Suppl Fig 2C).…”

MFG‐E8/integrin β3 signaling contributes to airway inflammation response and airway remodeling in an ovalbumin‐induced murine model of asthma

“…27 MFG-E8/integrin β3 may be involved in neuroinflammation and apoptotic changes after SAH. 24 It also has been reported that integrin β3 regulated the expression of Th2 cytokines in the rejecting transplant. 28 In addition, β3 integrin plays a critical role in vascular development/maturation and regulating the vascular sensitivity to VEGF in the heart.…”

Extracellular vesicles produced by bone marrow mesenchymal stem cells attenuate renal fibrosis, in part by inhibiting the RhoA/ROCK pathway, in a UUO rat model

“…Several recent studies have confirmed the therapeutic potential of MFG-E8 in various renal diseases, such as renal ischemiareperfusion injury and sepsis-induced acute kidney disease [51]. MFG-E8 has also been shown to protect the kidneys by suppressing inflammation and apoptosis [52,53]. Moreover, MFG-E8 plays an essential role in macrophage reprogramming through the induction of the anti-inflammatory M2 phenotype [19].…”