Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke

Factors influencing the decline in stroke mortality: A statement for healthcare professionals from the American Heart Association/American Stroke Association

Neuroinflammation and neurodegeneration often result from the aberrant deposition of aggregated host proteins, including amyloid‐β, α‐synuclein, and prions, that can activate inflammasomes. Inflammasomes function as intracellular sensors of both microbial pathogens and foreign as well as host‐derived danger signals. Upon activation, they induce an innate immune response by secreting the inflammatory cytokines interleukin (IL)‐1β and IL‐18, and additionally by inducing pyroptosis, a lytic cell death mode that releases additional inflammatory mediators. Microglia are the prominent innate immune cells in the brain for inflammasome activation. However, additional CNS‐resident cell types including astrocytes and neurons, as well as infiltrating myeloid cells from the periphery, express and activate inflammasomes. In this review, we will discuss current understanding of the role of inflammasomes in common degenerative diseases of the brain and highlight inflammasome‐targeted strategies that may potentially treat these diseases.

https://www.embopress.org/doi/epdf/10.15252/emmm.201810248

Inflammasomes in neuroinflammatory and neurodegenerative diseases.

Acute ischemic stroke is a common cause of morbidity and mortality worldwide. Thrombolysis with recombinant tissue plasminogen activator and endovascular thrombectomy are the main revascularization therapies for acute ischemic stroke. However, ischemia-reperfusion injury after revascularization therapy can result in worsening outcomes. Among all possible pathological mechanisms of ischemia-reperfusion injury, free radical damage (mainly oxidative/nitrosative stress injury) has been found to play a key role in the process. Free radicals lead to protein dysfunction, DNA damage, and lipid peroxidation, resulting in cell death. Additionally, free radical damage has a strong connection with inducing hemorrhagic transformation and cerebral edema, which are the major complications of revascularization therapy, and mainly influencing neurological outcomes due to the disruption of the blood-brain barrier. In order to get a better clinical prognosis, more and more studies focus on the pharmaceutical and nonpharmaceutical neuroprotective therapies against free radical damage. This review discusses the pathological mechanisms of free radicals in ischemia-reperfusion injury and adjunctive neuroprotective therapies combined with revascularization therapy against free radical damage.

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Free Radical Damage in Ischemia-Reperfusion Injury: An Obstacle in Acute Ischemic Stroke after Revascularization Therapy.

Ischemic stroke is a leading cause of morbidity and mortality worldwide. Resident microglia are the principal immune cells of the brain, and the first to respond to the pathophysiological changes induced by ischemic stroke. Traditionally, it has been thought that microglial activation is deleterious in ischemic stroke, and therapies to suppress it have been intensively explored. However, increasing evidence suggests that microglial activation is also critical for neurogenesis, angiogenesis, and synaptic remodeling, thereby promoting functional recovery after cerebral ischemia. Here, we comprehensively review the dual role of microglia during the different phases of ischemic stroke, and the possible mechanisms controlling the post-ischemic activity of microglia. In addition, we discuss the dynamic interactions between microglia and other cells, such as neurons, astrocytes, oligodendrocytes, and endothelial cells within the brain parenchyma and the neurovascular unit.

Dual Functions of Microglia in Ischemic Stroke

Nod-like receptor protein 3 (NLRP3) inflammasome is a crucial factor in mediating inflammatory responses after cerebral ischemia/reperfusion (I/R), but the cellular location of NLRP3 inflammasome in cerebral I/R has yet come to a conclusion, and there is still no specific evidence to state the relationship between mitochondria and the NLRP3 inflammasome in cerebral I/R In the present study, we detected the cellular localization of NLRP3 inflammasomes in a transient middle cerebral artery occlusion (tMCAO) rat model and a transwell co-culture cell system under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions Then, we investigated the relationship between mitochondrial dysfunction and the activation of NLRP3 inflammasomes in different cell types after OGD/R and cerebral I/R injury Our results showed that NLRP3 inflammasomes were first activated in microglia soon after cerebral I/R injury onset and then were expressed in neurons and microvascular endothelial cells later, but they were mainly in neurons Furthermore, mitochondrial dysfunction played an important role in activating NLRP3 inflammasomes in microglia after OGD/R, and mitochondrial protector could inhibit the activation of NLRP3 inflammasomes in cerebral I/R rats Our findings may provide novel insights into the cell type-dependent activation of NLRP3 inflammasomes at different stages of cerebral I/R injury and the role of mitochondrial dysfunction in activating the NLRP3 inflammasome pathway

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Mitochondrial dysfunction induces NLRP3 inflammasome activation during cerebral ischemia/reperfusion injury.

Stroke is a leading cause of disability with high morbidity and mortality worldwide. Of all strokes, 87% are ischemic. The only approved treatments for acute ischemic stroke are intravenous thrombolysis with alteplase within 4.5 h and thrombectomy within 8 h after symptom onset, which can be applied to just a few patients. During the past decades, ischemic preconditioning has been widely studied to confirm its neuroprotection against subsequent ischemia/reperfusion injury in the brain, including preconditioning in situ or in a remote organ (such as a limb) before onset of brain ischemia, the latter of which is termed as remote ischemic preconditioning. Because acute stroke is unpredicted, ischemic preconditioning is actually not suitable for clinical application. So remote ischemic conditioning performed during or after the ischemic duration of the brain was then designed to study its neuroprotection alone or in combination with alteplase in animals and patients, which is named as remote ischemic perconditioning or remote ischemic postconditioning. As expected, animal experiments and clinical trials both showed exciting results, indicating that an evolution in the treatment for acute ischemic stroke may not be far away. However, some problems or disputes still exist. This review summarizes the research progress and unresolved issues of remote ischemic conditioning (pre-, per-, and post-conditioning) in treating acute ischemic stroke, with the hope of advancing our understanding of this promising neuroprotective strategy for ischemic stroke in the near future.

Remote ischemic conditioning for acute ischemic stroke: dawn in the darkness.

Stroke is an important disease that is prevalent worldwide [1–3]. Ischemic stroke accounts for 80% of stroke cases. Currently, evidence-based effective treatments for ischemic stroke are limited, and only intravenous thrombolysis with Alteplase (a commercially available thrombolytic agent) within 4.5 h of stroke onset and thrombectomy and arterial thrombolysis within 6–24 h of onset are effective [4, 5]. However, because these two treatments have strict indications and certain risks (reperfusion injury and bleeding) [5–8], there is an urgent need to develop new treatment methods. Thus, comprehensive elucidation of the molecular mechanisms underlying ischemic brain damage and the search for key signaling pathways and protein molecules are important for guiding the clinical treatment of ischemic stroke. The inflammatory reaction is an important pathophysiological mechanism underlying cerebral ischemic injury. The inflammatory reaction after cerebral ischemia influences the development of ischemic injury and is considered to be a key element related to lesion progression. Both permanent ischemia and reperfusion after transient ischemia have been shown to induce inflammatory reactions in cerebral tissues [9]. However, the pathophysiological processes of these two ischemic conditions are different [10], and the severity of the inflammatory reactions also differ. An inflammatory reaction can be initiated within several hours of stroke onset and can last for several days or even longer [11]. Therefore, treatments targeting the inflammatory reactions have a longer time window and excellent prospects for clinical application. Cells in the ischemic core undergo necrosis within a short time after cerebral artery occlusion, whereas cells in the surrounding area (ischemic penumbra) can survive for several hours [12]. Restoration of blood flow within this time window may allow cells to survive but may also result in irreversible cell death (reperfusion injury) [12]. For several minutes to several hours during cerebral ischemia, dead cells release danger signals, such as purines, high mobility group box 1 protein, heat shock proteins, and peroxiredoxin family proteins [13]. These danger signals bind to the receptors in the cell membrane or intracellular receptors of adjacent cells to initiate innate immune responses, resulting in inflammatory reactions [13]. These endogenous danger signaling molecules are known as damage-associated molecular patterns (DAMPs). The receptors that recognize DAMPs are known as pattern recognition receptors (PRRs) and mainly include families such as the Toll-like receptors and Nod-like receptors (NLRs) [14]. DAMPs released by necrotic cells in the ischemic core are the source of signals that initiate inflammatory reactions. However, the sources of the danger signals that promote further development of the inflammatory reactions and how they exert their functions are still unclear. Cells in the ischemic penumbra are thought to undergo apoptosis, which can last for several weeks [15]. Zhaofei Dong and Kuang Pan have contributed equally to this work.

The Possibility and Molecular Mechanisms of Cell Pyroptosis After Cerebral Ischemia

Idebenone attenuates cerebral inflammatory injury in ischemia and reperfusion via dampening NLRP3 inflammasome activity.

Most circular RNAs (circRNAs) belong to a novel class of noncoding RNAs that are produced by back-splicing reactions, and they regulate physiological and pathophysiological processes in human disease. Although circRNA expression has been shown to be altered in the ischemic cerebral tissue in animal studies, the expression profile of circRNA in the patients with acute ischemic stroke (AIS) has not been investigated to date. In this investigation, high-throughput sequencing was carried out to compare the circRNA expression of peripheral blood mononuclear cells (PBMCs) from five patients with AIS and five healthy subjects. A total of 521 circRNAs were expressed differentially between the patients with AIS and healthy controls (p < .05, fold difference ≥2) including 373 upregulated circRNAs and 148 downregulated circRNAs in patients with AIS compared to controls. Thirteen candidate circRNAs were verified by quantitative real-time polymerase chain reaction (qRT-PCR). Bioinformatics analyses showed that these differentially expressed circRNAs were highly conserved, as well as eight circRNAs that were confirmed by qRT-PCR containing binding sites to multiple microRNAs. Kyoto Encyclopedia of Genes and Genomes pathway enrichment and gene ontology analyses indicated that the aberrantly expressed circRNAs participated in many pathophysiological processes of AIS, especially regarding inflammation and immunity. In conclusion, patients with AIS differentially express certain circRNAs in PBMCs, which may be diagnostic biomarkers or potential therapeutic targets.

Jingrui Pan

Papers

Mitochondrial dysfunction induces NLRP3 inflammasome activation during cerebral ischemia/reperfusion injury.

Remote ischemic conditioning for acute ischemic stroke: dawn in the darkness.

The Possibility and Molecular Mechanisms of Cell Pyroptosis After Cerebral Ischemia

Idebenone attenuates cerebral inflammatory injury in ischemia and reperfusion via dampening NLRP3 inflammasome activity.

CircRNA expression profiles and function prediction in peripheral blood mononuclear cells of patients with acute ischemic stroke