Posts Tagged: blood–brain barrier

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Xiaoming Hu, T. Michael De Silva, Jun Chen, Frank M. Faraci

Structural alterations in endothelial cells are critical for blood–brain barrier (BBB) opening early after ischemic stroke. A, The opening of paracellular pathways: cytoskeletal rearrangements and related signaling in endothelial cells. B, The transcellular pathway of BBB leakage. ADF indicates actin-depolymerizing factor; CaM, calmodulin; LIMK, LIM kinase; MLC, myosin light chain; MLCK, MLC kinase; MLCP, MLC phosphatase; MMP, matrix metallopeptidase; ROCK: Rho kinase; TESK1, testicular protein kinase 1; and ZO, zonula occluden. [Powerpoint File]

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Xiaoming Hu, T. Michael De Silva, Jun Chen, Frank M. Faraci

Pericytes play multifaceted roles in ischemia and reperfusion. Pericytes display both beneficial and detrimental functions during ischemia and reperfusion phases, and contribute significantly to the blood–brain barrier damage and repair. 1. Pericyte contraction and dilation regulate cerebral blood flow in the ischemic and perilesion areas. 2. Pericyte protects other neurovascular unit (NVU) components through releasing protective/trophic factors such as nerve growth factor (NGF), neurotrophin-3 (NT-3), vascular endothelial growth factor (VEGF), angiopoietin (Ang-1), and glial cell line-derived neurotrophic factor (GDNF). 3. Phagocytotic pericytes help to eliminate dead or injured tissue in the ischemic core, which in turn mitigates local inflammation and reduce secondary tissue damage. 4. Pericyte–endothelial cell interaction promotes angiogenesis after stroke. 5) Pericytes have the potential to serve as an origin of NVU components during tissue repair after ischemic stroke. Illustration credit: Ben Smith. [Powerpoint File]

Inflammatory Disequilibrium in Stroke

Inflammatory Disequilibrium in Stroke

Danica Petrovic-Djergovic*, Sascha N. Goonewardena*, David J. Pinsky

Inflammatory disequilibrium after stroke. After brain ischemia, circulating cells such as neutrophils, monocytes (innate immune cells), T cells (adaptive immune cells) interact with platelets, causing sludging and cessation of cerebral blood flow and tissue hypoxia. Acute ischemia refers to the early phases (minutes to hours) and delayed refers to late phases of the ischemic process (hours to days). Endothelial cell activation promotes immune cell transmigration into the injured brain parenchyma. In acute phase of brain ischemia, infiltrating immune cells (neutrophils, monocytes, dendritic cells, and T cells) and resident brain cells (microglia and astrocytes) are activated and promote tissue injury. Activated monocytes adhere to activated endothelium and after transmigration into the brain tissue transform into the blood-borne macrophages. Macrophages generate reactive oxygen intermediates, secrete proinflammatory cytokines, upregulate costimulatory molecules (CD80 shown here), and create a prothrombotic environment. Similarly, microglia migrates toward the lesion site early on after the insult and secretes proinflammatory mediators that cause additional injury; however, microglia promotes tissue repair and remodeling through debris phagocytosis. Astrocytes can secrete both proinflammatory (CXC-chemokine ligand [CXCL10], monocyte chemoattractant protein-1 [MCP-1]) as well anti-inflammatory (interleukin [IL]-10, transforming growth factor-β [TGF-β]) chemokines/cytokines to promote injury or repair, respectively; IL-23 produced by macrophages/microglia activate γδT-cells, which contributes to tissue injury via secretion of IL-17; Naïve T-cells (CD4/CD8) contribute to brain injury in an antigen unspecific manner, possibly via interferon-γ (INF-γ), reactive oxygen species (ROS), and perforin. Other T cells such as T-regulatory cells (T-regs) induce brain tissue repair via IL-10 secretion, inhibition of the effector T-cells response, neurogenesis, and central nervous system (CNS) tissue antigen tolerization. In the delayed phase after brain ischemia, antigen-presenting cells (APC), that is, macrophages, microglia, astrocytes, and dendritic cells (not depicted in the schematic), present CNS antigens to CD4+ or CD8+ T cells in antigen-specific manner in context of major histocompatibility complex (MHC) class I or II. Purinergic mediators such as ATP and adenosine act as an extracellular danger signals differentially influencing immune responses in stroke. Ectoenzymes, cluster of differentiation 39 (CD39), and cluster of differentiation 73 (CD73) act in tandem to dissipate proinflammatory and generate anti-inflammatory mediators. Brain resident cells and certain immune cells express these ectoenzymes. ICAM indicates intercellular adhesion molecule-1; MMP, matrix metalloproteinases; mo-MФs, monocytes–macrophages; and NET, neutrophil extracellular trap. [Powerpoint File]