Abstract TMP68: A Pro-inflammatory Monocyte Subset (ccr2+/ly6c
            hi
            ) Is Dominantly Recruited Into Acute Ischemic Brain.

Post-ischemic inflammation has been associated with ischemic brain injury. Infiltrated peripheral immune cells including monocytes/macrophages (MMs) contribute to the stroke-induced inflammation. MM mobilization from the periphery to the brain (MM trafficking) involves spleen, as an immediate storage of monocytes and the circulatory system as a conduit for their transport; however, there has been no systematic analysis of MM trafficking in stroke. There are two monocyte subsets, a pro-inflammatory (CCR2+/Ly6C hi ) and an anti-inflammatory (CCR2-/Ly6C lo ). These are sequentially recruited to the injury site in a controlled manner to elicit inflammation and repair/healing respectively. Current study determines the extent of trafficking of the monocyte subsets upon stroke and the role of the subsets on stroke-induced brain injury. Eleven week-old C57BL mice were subjected to transient middle cerebral artery occlusion and then leukocytes were isolated from blood, spleen, and brain prior to, 1d-, and 3d-post ischemia. The cells were incubated with antibodies (lineage marker or CD45 and CD11b to detect MMs, and Ly6C) and then analyzed using flow cytometry/FACS. We observed decreased spleen size following ischemia (>40% reduction in spleen weight at 1d- and 3d-post). Both Ly6C hi and Ly6C lo MM number in the spleen and blood were significantly decreased in 1d-post ischemic mice, and these levels were sustained until 3d-post ischemia. On the other hand, brain MM numbers were increased at 1d-post and further increased at 3d-post ischemia (Fig. 1). Importantly, the Ly6C hi subset was dominantly increased in the ischemic brain compared to Ly6C lo subset (Fig. 2). The findings of MM trafficking and predominant increase in Ly6C hi MMs in the ischemic brain indicate that the pro-inflammatory monocyte subset might have a critical role in acute ischemic brain injury. Selective targeting of pro-inflammatory subset is suggested to reduce acute stroke-induced brain injury.

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Critical role of microvasculature basal lamina in ischemic brain injury

Progress in Neurobiology ◽

10.1016/j.pneurobio.2007.07.006 ◽

2007 ◽

Vol 83 (3) ◽

pp. 140-148 ◽

Cited By ~ 60

Author(s):

Chen Xu Wang ◽

Ashfaq Shuaib

Keyword(s):

Brain Injury ◽

Basal Lamina ◽

Critical Role ◽

Ischemic Brain Injury ◽

Ischemic Brain

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Interruption of Endolysosomal Trafficking After Focal Brain Ischemia

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.719100 ◽

2021 ◽

Vol 14 ◽

Author(s):

Kurt Hu ◽

Bhakta Prasad Gaire ◽

Lalita Subedi ◽

Awadhesh Arya ◽

Hironori Teramoto ◽

...

Keyword(s):

Brain Injury ◽

Membrane Fusion ◽

Brain Ischemia ◽

Critical Role ◽

Ischemic Brain Injury ◽

Synaptic Connections ◽

Attachment Protein ◽

Ischemic Brain ◽

Early Endosomes ◽

The Brain

A typical neuron consists of a soma, a single axon with numerous nerve terminals, and multiple dendritic trunks with numerous branches. Each of the 100 billion neurons in the brain has on average 7,000 synaptic connections to other neurons. The neuronal endolysosomal compartments for the degradation of axonal and dendritic waste are located in the soma region. That means that all autophagosomal and endosomal cargos from 7,000 synaptic connections must be transported to the soma region for degradation. For that reason, neuronal endolysosomal degradation is an extraordinarily demanding and dynamic event, and thus is highly susceptible to many pathological conditions. Dysfunction in the endolysosomal trafficking pathways occurs in virtually all neurodegenerative diseases. Most lysosomal storage disorders (LSDs) with defects in the endolysosomal system preferentially affect the central nervous system (CNS). Recently, significant progress has been made in understanding the role that the endolysosomal trafficking pathways play after brain ischemia. Brain ischemia damages the membrane fusion machinery co-operated by N-ethylmaleimide sensitive factor (NSF), soluble NSF attachment protein (SNAP), and soluble NSF attachment protein receptors (SNAREs), thus interrupting the membrane-to-membrane fusion between the late endosome and terminal lysosome. This interruption obstructs all incoming traffic. Consequently, both the size and number of endolysosomal structures, autophagosomes, early endosomes, and intra-neuronal protein aggregates are increased extensively in post-ischemic neurons. This cascade of events eventually damages the endolysosomal structures to release hydrolases leading to ischemic brain injury. Gene knockout and selective inhibition of key endolysosomal cathepsins protects the brain from ischemic injury. This review aims to provide an update of the current knowledge, future research directions, and the clinical implications regarding the critical role of the neuronal endolysosomal trafficking pathways in ischemic brain injury.

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Critical role of PTEN in the coupling between PI3K/Akt and JNK1/2 signaling in ischemic brain injury

FEBS Letters ◽

10.1016/j.febslet.2006.12.055 ◽

2007 ◽

Vol 581 (3) ◽

pp. 495-505 ◽

Cited By ~ 59

Author(s):

Quan-Guang Zhang ◽

Dong-Na Wu ◽

Dong Han ◽

Guang-Yi Zhang

Keyword(s):

Brain Injury ◽

Critical Role ◽

Ischemic Brain Injury ◽

Ischemic Brain

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Sulfide catabolism ameliorates hypoxic brain injury

Nature Communications ◽

10.1038/s41467-021-23363-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Eizo Marutani ◽

Masanobu Morita ◽

Shuichi Hirai ◽

Shinichi Kai ◽

Robert M. H. Grange ◽

...

Keyword(s):

Brain Injury ◽

Mitochondrial Respiration ◽

Energy Homeostasis ◽

Critical Role ◽

Ground Squirrels ◽

Mammalian Brain ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Sulfide:Quinone Oxidoreductase ◽

The Brain

AbstractThe mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain’s sensitivity to hypoxia is incompletely understood. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide. Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury.

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