Astrocyte-Derived Pentraxin 3 Supports Blood–Brain Barrier Integrity Under Acute Phase of Stroke

Abstract

Background and Purpose Pentraxin 3 (PTX3) is released upon inflammatory responses in many organs. However, roles of PTX3 in brain are still mostly unknown. Here we asked whether and how PTX3 contributes to blood-brain barrier (BBB) dysfunction during the acute phase of ischemic stroke. Methods In vivo, spontaneously hypertensive rats were subjected to focal cerebral ischemia by transient middle cerebral artery occlusion. At day 3, brains were analyzed to evaluate the cellular origin of PTX3 expression. Correlations with BBB breakdown were assessed by IgG staining. In vitro, rat primary astrocytes and rat brain endothelial RBE.4 cells were cultured to study the role of astrocyte-derived PTX3 on VEGF-mediated endothelial permeability. Results During the acute phase of stroke, reactive astrocytes in the peri-infarct area expressed PTX3. There was negative correlation between gradients of IgG leakage and PTX3-positive astrocytes. Cell culture experiments showed that astrocyte-conditioned media increased levels of tight junction proteins and reduced endothelial permeability under normal conditions. Removing PTX3 from astrocyte-conditioned media by immunoprecipitation increased endothelial permeability. PTX3 strongly bound VEGF in vitro and was able to decrease VEGF-induced endothelial permeability. Conclusions Astrocytes in peri-infarct areas upregulate PTX3 which may support BBB integrity by regulating VEGF-related mechanisms. This response in astrocytes may comprise a compensatory mechanism for maintaining BBB function after ischemic stroke.

Depletion of microglia exacerbates postischemic inflammation and brain injury

“…59,60 In addition to these properties, astrocytes acquire the capacity for producing pro-inflammatory factors and antigen-presentation upon brain ischemia. 61,62 This suggests the possibility that activation of astrocyte may promotes ischemic brain injury.…”

Accumulation of α-Synuclein in Cerebellar Purkinje Cells of Diabetic Rats and Its Potential Relationship with Inflammation and Oxidative Stress Markers

“…Additionally, it has been reported that the levels of acute phase protein increased in a variety of neurodegenerative diseases [36, 37]. For instance, Lee et al have observed high plasma PTX3 levels in idiopathic PD patients and found significant correlation between the PTX3 levels and daily life activities and motor functions [38].…”

Stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms

“…These exosomes, when isolated from BM-MSCs, appear to be 50–100 nm in size, display CD81, CD9, and Alix exosome-associated proteins, and have a lipid membrane identity consisting of cholesterol, sphingomyelin, and phosphatidylcholine (Lai et al, 2010). BM-MSCs express multiple trophic factors which may function to protect and support neurons in ischemic conditions, including BDNF, NGF, thrombospondin1, pantraxin3, VEGF, bFGF, and placental growth factor, as well as therapeutic microRNAs, such as microRNA 133b (Eckert et al, 2013; Park et al, 2015; Shichinohe et al, 2016; Xin et al, 2016). Importantly, BM-MSCs play a potent role in the sequestration of neuroinflammation.…”

“…From the data available, we can postulate that if these cells, which can differentiate into endothelial-like cells, do regulate the immune environment post-stroke, such effects might arise via restoration of the BBB and its subsequent decreased permeability to circulating inflammatory cell types or general paracrine effects on pro-inflammatory immune sources (Borlongan et al, 2012; Garbuzova-Davis et al, 2014). In addition, because breast milk-derived stem cells can differentiate into astrocytes, which can produce pentraxin 3, a compound that promotes BBB integrity after ischemic stroke, breast milk-derived stem cells may have the capacity to encourage suppression of peripheral immune invasion (Shindo et al, 2016). To this end, an active component in breast milk, milk fat globule-EGF factor 8 protein, has anti-inflammatory effects in models of inflammatory bone loss, suggesting, perhaps, an a role for breast milk-derived components in abrogating neuroinflammation following stroke (Abe et al, 2014).…”