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Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed "resting microglia." Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the "activated microglial cell." This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

Physiology of Microglia

This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell dea...

Ischemic Cell Death in Brain Neurons

In the adult brain, new neurons are continuously generated in the subventricular zone and dentate gyrus, but it is unknown whether these neurons can replace those lost following damage or disease. Here we show that stroke, caused by transient middle cerebral artery occlusion in adult rats, leads to a marked increase of cell proliferation in the subventricular zone. Stroke-generated new neurons, as well as neuroblasts probably already formed before the insult, migrate into the severely damaged area of the striatum, where they express markers of developing and mature, striatal medium-sized spiny neurons. Thus, stroke induces differentiation of new neurons into the phenotype of most of the neurons destroyed by the ischemic lesion. Here we show that the adult brain has the capacity for self-repair after insults causing extensive neuronal death. If the new neurons are functional and their formation can be stimulated, a novel therapeutic strategy might be developed for stroke in humans.

/pdf/neuronal-replacement-from-endogenous-precursors-in-the-adult-4ghf3i2h7x.pdf

Neuronal replacement from endogenous precursors in the adult brain after stroke

Ischemia and reperfusion-elicited tissue injury contributes to morbidity and mortality in a wide range of pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease and sleep apnea. Ischemia-reperfusion injury is also a major challenge during organ transplantation and cardiothoracic, vascular and general surgery. An imbalance in metabolic supply and demand within the ischemic organ results in profound tissue hypoxia and microvascular dysfunction. Subsequent reperfusion further enhances the activation of innate and adaptive immune responses and cell death programs. Recent advances in understanding the molecular and immunological consequences of ischemia and reperfusion may lead to innovative therapeutic strategies for treating patients with ischemia and reperfusion-associated tissue inflammation and organ dysfunction.

/pdf/ischemia-and-reperfusion-from-mechanism-to-translation-1v2cagcnsb.pdf

Ischemia and reperfusion—from mechanism to translation

Inflammation and glial responses in ischemic brain lesions

Lesions in the nervous system induce rapid activation of glial cells and under certain conditions additional recruitment of granulocytes, T-cells and monocytes/macrophages from the blood stream triggered by upregulation of cell adhesion molecules, chemokines and cytokines. Hematogenous cell infiltration is not restricted to infectious or autoimmune disorders of the nervous system, but also occurs in response to cerebral ischemia and traumatic lesions. Neuroinflammation can cause neuronal damage, but also confers neuroprotection. Granulocytes occlude vessels during reperfusion after transient focal ischemia, while the functional role of T-cells and macrophages in stroke development awaits further clarification. After focal cerebral ischemia neurotoxic mediators released by microglia such as the inducible nitric oxide synthase (leading to NO synthesis) and the cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are upregulated prior to cellular inflammation in the evolving lesion and functionally contribute to secondary infarct growth as revealed by numerous pharmacological experiments and by use of transgenic animals. On the other hand, cytokine induction remote from ischemic lesions involves NMDA-mediated signalling pathways and confers neuroprotection. After nerve injury T cells can rescue CNS neurons. In the peripheral nervous system neuroinflammation is a prerequisite for successful regeneration that is impeded in the CNS. In conclusion, there is increasing evidence that neuroinflammation represents a double edged sword. The opposing neurotoxic and neuroprotective properties of neuroinflammation during CNS injury provide arich and currently unexplored set of research problems.

Detrimental and Beneficial Effects of Injury-Induced Inflammation and Cytokine Expression in the Nervous System

The contribution of the immune system to the pathogenesis of ischemic lesions is still uncertain. We have analyzed leukocyte infiltration in photochemically induced focal ischemia of the rat parietal cortex by immunocytochemistry. Between 1 and 2 days after photothrombosis, CD5+ T cells adhered to subpial and cortical vessels and infiltrated the ischemic lesion prior to macrophages. By day 3 numerous T cells and some macrophages, whose number increased further between day 3 and day 7, had infiltrated the border zone around the lesion sparing the center. In addition, CD5-/CD8+ lymphocytes that probably represent natural killer cells were found. Intercellular adhesion molecule-1 (ICAM-1) was expressed on endothelial cells on days 1 and 2 and in the border zone on infiltrating leukocytes from day 3 to day 7. Starting on day 7, macrophages infiltrated the core of the lesion to remove debris. When the entire lesion was covered by macrophages at day 14, the number of T cells had decreased and ICAM-1 immunoreactivity was no longer found in or around the infarct. In conclusion, our study shows that ischemic lesions can lead to a local immune reaction in the CNS. Thus, blocking of lymphocyte-derived cytokines or cell adhesion molecules may provide a new approach to confining the sequelae of stroke.

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1995.5

Lymphocytic Infiltration and Expression of Intercellular Adhesion Molecule-1 in Photochemically Induced Ischemia of the Rat Cortex

Local immune responses in the rat cerebral cortex after middle cerebral artery occlusion

Inflammation contributes to brain damage caused by ischaemic stroke. Macrophages, as the prevailing inflammatory cell population in stroke lesions, can be visualized using ultrasmall superparamagnetic iron oxide (USPIO) as a cell-specific contrast agent for MRI. In this single-centre open-labelled clinical phase II study we tested the potential of USPIO-enhanced MRI for macrophage imaging in human ischaemic stroke lesions. In a series of 10 consecutive patients, USPIO contrast agent was infused at the end of the first week after symptom onset. Two follow-up MRI scans were performed 24-36 h and 48-72 h after infusion. Two distinct components of USPIO-related signal changes were discernible, one associated with blood vessels and one representing parenchymal enhancement. Vessel-associated changes appeared as signal loss on T2/T2*-weighted images and decreased from the first to second scan after USPIO infusion, most likely reflecting a transient blood pool effect of the contrast agent. Conversely, parenchymal enhancement was mainly evident on T1-weighted images, increased over time, and matched with the expected distribution of macrophages. Importantly, USPIO-induced signal alterations throughout differed from signatures of conventional gadolinium-enhanced MRI, thus being independent from breakdown of the blood-brain barrier. We suggest that increasing USPIO-enhancement on T1-weighted images indicates brain infiltration by USPIO-laden macrophages. Thus, USPIO-enhanced MRI may provide an in vivo surrogate marker of cellular inflammation in stroke and other CNS pathologies.

Michael Schroeter

Papers

Inflammation and glial responses in ischemic brain lesions

Detrimental and Beneficial Effects of Injury-Induced Inflammation and Cytokine Expression in the Nervous System

Lymphocytic Infiltration and Expression of Intercellular Adhesion Molecule-1 in Photochemically Induced Ischemia of the Rat Cortex

Local immune responses in the rat cerebral cortex after middle cerebral artery occlusion

In vivo MRI of brain inflammation in human ischaemic stroke