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MerTK and MFG-E8 are transiently up-regulated after focal cerebral ischemia. (A) MerTK is highly expressed 3 d after ischemia and colocalizes with activated microglia/macrophages (isolectinB4; but not astrocytic or neuronal markers). Staining is absent on the contralateral side and in MerTK mutant rats, which harbor a deletion of the MerTK gene. (B) MFG-E8 staining shows protein expression 3 and 7 d after focal cortical ischemia, which is absent on the contralateral side and in Mfge8 knockout mice. MFG-E8 colocalizes with activated macrophages/ microglia (isolectin-B4), but also neurons (NeuN, Right, yellow arrows), consistent with its function as a bridging protein. (Scale bars, 10 μm.) Five animals were analyzed per condition.
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Brain ischemia is a major cause of death and disability worldwide, but the cellular mechanisms of delayed neuronal loss and brain atrophy after cerebral ischemia are poorly understood and thus currently untreatable. Surprisingly, we find that after cerebral ischemia, brain macrophages phagocytose viable and functional neurons, causing...
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... the infarct region at 1, 3, 7, and 28 d, MerTK staining was only detectable by immunohistochemistry at 3 d af- ter ischemia in rats (Fig. 1A), with MFG-E8 levels also being strongly increased at 3 d (Fig. S1). Similar results were obtained after cortical ischemia in mice, where MFG-E8 levels remained increased at 7 d (Fig. 1B and Fig. S1). Immunoreactivity for MerTK or MFG-E8 was virtually absent in the contralateral (vehicle-injected) hemisphere (Fig. 1). Thus, these two ...
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... the infarct region at 1, 3, 7, and 28 d, MerTK staining was only detectable by immunohistochemistry at 3 d af- ter ischemia in rats (Fig. 1A), with MFG-E8 levels also being strongly increased at 3 d (Fig. S1). Similar results were obtained after cortical ischemia in mice, where MFG-E8 levels remained increased at 7 d (Fig. 1B and Fig. S1). Immunoreactivity for MerTK or MFG-E8 was virtually absent in the contralateral (vehicle-injected) hemisphere (Fig. 1). Thus, these two phago- cytic proteins are minimally expressed in the naïve brain, but ...
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... the infarct region at 1, 3, 7, and 28 d, MerTK staining was only detectable by immunohistochemistry at 3 d af- ter ischemia in rats (Fig. 1A), with MFG-E8 levels also being strongly increased at 3 d (Fig. S1). Similar results were obtained after cortical ischemia in mice, where MFG-E8 levels remained increased at 7 d (Fig. 1B and Fig. S1). Immunoreactivity for MerTK or MFG-E8 was virtually absent in the contralateral (vehicle-injected) hemisphere (Fig. 1). Thus, these two phago- cytic proteins are minimally expressed in the naïve brain, but are strongly and transiently expressed in the infarct at 3-7 d after- ...
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... 3 d af- ter ischemia in rats (Fig. 1A), with MFG-E8 levels also being strongly increased at 3 d (Fig. S1). Similar results were obtained after cortical ischemia in mice, where MFG-E8 levels remained increased at 7 d (Fig. 1B and Fig. S1). Immunoreactivity for MerTK or MFG-E8 was virtually absent in the contralateral (vehicle-injected) hemisphere (Fig. 1). Thus, these two phago- cytic proteins are minimally expressed in the naïve brain, but are strongly and transiently expressed in the infarct at 3-7 d after- ...
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... protein levels of MerTK and MFG-E8 coincided with activation of microglia/macrophages (hereafter referred to only as microglia), as detected by their affinity for isolectin-B4 (28,29). MerTK was only detectable in activated microglia, and MFG-E8 was additionally found to opsonize neurons (Fig. 1B and Fig. S1), in accordance with its function in bridging micro- glial receptors and PS-exposing neurons. Furthermore, staining for β-galactosidase expressed under the endogenous milk fat globule-EGF factor 8 (Mfge8) promoter in Mfge8 knockout mice (30) showed protein expression at 3 and 7 d after focal ischemia in both astrocytes and microglia ...
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... accordance with its function in bridging micro- glial receptors and PS-exposing neurons. Furthermore, staining for β-galactosidase expressed under the endogenous milk fat globule-EGF factor 8 (Mfge8) promoter in Mfge8 knockout mice (30) showed protein expression at 3 and 7 d after focal ischemia in both astrocytes and microglia (but not neurons) (Fig. S1), as has been reported during other conditions of brain inflammation (9, 31). Of note, MerTK staining was absent in the brains of Royal College of Surgeons rats, which harbor a MerTK gene deletion (32), and MFG-E8 staining was absent from Mfge8 knockout mice (30) subjected to endothelin-1 induced ischemia (Fig. 1), confirming antibody ...
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... and microglia (but not neurons) (Fig. S1), as has been reported during other conditions of brain inflammation (9, 31). Of note, MerTK staining was absent in the brains of Royal College of Surgeons rats, which harbor a MerTK gene deletion (32), and MFG-E8 staining was absent from Mfge8 knockout mice (30) subjected to endothelin-1 induced ischemia (Fig. 1), confirming antibody specificity. However, Mfge8 knockout ani- mals showed pronounced MerTK expression and vice versa (Fig. S1), indicating independent expression of these ...
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... MerTK staining was absent in the brains of Royal College of Surgeons rats, which harbor a MerTK gene deletion (32), and MFG-E8 staining was absent from Mfge8 knockout mice (30) subjected to endothelin-1 induced ischemia (Fig. 1), confirming antibody specificity. However, Mfge8 knockout ani- mals showed pronounced MerTK expression and vice versa (Fig. S1), indicating independent expression of these ...
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... CD68 + phagolysosomes in the MerTK mutant compared with wild-type animals (Fig. S4), indicating that the phagocytic activity was reduced in MerTK mutant microglia when the density of neurons was declining most rapidly. No differences were ob- served at other time-points, in line with the absence of MerTK expression at these other time-points (Fig. ...
Citations
... PS expression may occur due to oxidative stress, increased calcium levels, or ATP depletion [51]. Neurons expressing PS are recognized by opsonins such as milk fat globule EGF-like factor 8 (MFG-E8) and vitronectin receptors or growth arrest-specific factor 6 and Mer receptor tyrosine kinase (MERTK) receptors [52,53]. Additionally, the presence of calreticulin on the cell surface, as a result of ER stress, can serve as an "eat me" signal [54]. ...
The majority of approved therapies for many diseases are developed to target their underlying pathophysiology. Understanding disease pathophysiology has thus proven vital to the successful development of clinically useful medications. Stroke is generally accepted as the leading cause of adult disability globally and ischemic stroke accounts for the most common form of the two main stroke types. Despite its health and socioeconomic burden, there is still minimal availability of effective pharmacological therapies for its treatment. In this review, we take an in-depth look at the etiology and pathophysiology of ischemic stroke, including molecular and cellular changes. This is followed by a highlight of drugs, cellular therapies, and complementary medicines that are approved or undergoing clinical trials for the treatment and management of ischemic stroke. We also identify unexplored potential targets in stroke pathogenesis that can be exploited to increase the pool of effective anti-stroke and neuroprotective agents through de novo drug development and drug repurposing.
... One role of microglia is to phagocytose viral particles following infection (Chhatbar and Prinz, 2021), as would be expected under our experimental conditions. However, phagocytosis of apparently healthy neurons can occur under inflammatory conditions (Fricker et al., 2012a;Neher et al., 2013) and neurons under stress, perhaps from expression of foreign proteins such as opsin/GFP constructs, can lead to the aberrant presentation of proteins and phospholipids on the neuronal surface, triggering phagocytosis (Wang and Neumann, 2010;Fricker et al., 2012b). ...
Introduction: Expression of light sensitive ion channels by selected neurons has been achieved by viral mediated transduction with gene constructs, but for this to have therapeutic uses, for instance in treating epilepsy, any adverse effects of viral infection on the cerebral cortex needs to be evaluated. Here, we assessed the impact of adeno-associated virus 8 (AAV8) carrying DNA code for a soma targeting light activated chloride channel/FusionRed (FR) construct under the CKIIa promoter. Methods: Viral constructs were harvested from transfected HEK293 cells in vitro and purified. To test functionality of the opsin, cultured rodent neurons were transduced and the light response of transduced neurons was assayed using whole-cell patch-clamp recordings. In vivo expression was confirmed by immunofluorescence for FR. Unilateral intracranial injections of the viral construct were made into the mouse neocortex and non-invasive fluorescence imaging of FR expression made over 1-4 weeks post-injection using an IVIS Spectrum system. Sections were also prepared from injected mouse cortex for immunofluorescence staining of FR, alongside glial and neuronal marker proteins. Results: In vitro, cortical neurons were successfully transduced, showing appropriate physiological responses to light stimulation. Following injections in vivo, transduction was progressively established around a focal injection site over a 4-week period with spread of transduction proportional to the concentration of virus introduced. Elevated GFAP immunoreactivity, a marker for reactive astrocytes, was detected near injection sites associated with, and proportional to, local FR expression. Similarly, we observed reactive microglia around FR expressing cells. However, we found that the numbers of NeuN+ neurons were conserved close to the injection site, indicating that there was little or no neuronal loss. In control mice, injected with saline only, astrocytosis and microgliosis was limited to the immediate vicinity of the injection site. Injections of opsin negative viral constructs resulted in comparable levels of astrocytic reaction as seen with opsin positive constructs. Discussion: We conclude that introduction of an AAV8 vector transducing expression of a transgene under a neuron specific promotor evokes a mild inflammatory reaction in cortical tissue without causing extensive short-term neuronal loss. The expression of an opsin in addition to a fluorescent protein does not significantly increase neuroinflammation. Trevelyan AJ and Clowry GJ (2024) AAV8 vector induced gliosis following neuronal transgene expression.
... Whether the phagocytic function of microglia in stroke is advantageous or detrimental remains uncertain, emphasizing the importance of maintaining a delicate balance for an improved stroke prognosis. Specifically, some studies reported that enhancing the phagocytic capability of microglia in a MCAO model can foster efficient clearance of tissue debris [48], while others report that hyperreactive microglia can engulf live or stressed neuronal cells and result in worsened neurological deficits [49]. Notably, previous studies from our group (data not shown) have demonstrated that while wild-type microglia produce neurotrophic and regenerative mediators, and efficiently eliminate debris, cortistatin-deficient microglia exert deficient phagocytosis in physiological and demyelinating environments [50]. ...
Ischemic stroke is the result of a permanent or transient occlusion of a brain artery, leading to irreversible tissue injury and long-term sequelae. Despite ongoing improvements, therapeutic failure remains notorious, and stroke remains the second leading cause of death worldwide. Neuroinflammation, blood-brain barrier (BBB) breakdown, and immune deregulation are the major hallmarks of the pathogenesis and outcomes of brain ischemia. Understanding the interconnected and complex mechanisms and the endogenous mediators that globally modulate these responses is essential for developing successful therapeutic strategies. In this context, our study focuses on cortistatin, a neuropeptide widely distributed in the central nervous and immune systems. The anti-inflammatory, immunomodulatory, and neuroprotective properties of cortistatin make it an attractive novel therapeutic agent against ischemic stroke. To this aim, we evaluated the potential effect of cortistatin in the widely-known preclinical model of stroke MCAO (middle cerebral artery occlusion) in young (3 months old) and middle-aged (6 months old) wild-type mice. We observed that late treatment with cortistatin (24 h after stroke) improved neurological score, induced smaller lesions, reduced/modulated glial response, astrocytic scar formation and BBB recovery, and decreased peripheral immune activity. This beneficial effect of cortistatin suggests that multimodal-based therapies may represent a novel treatment for ischemic stroke, holding great promise compared to interventions targeting only a single aspect of stroke pathophysiology. Moreover, we found that the absence of cortistatin in young and middle-aged cortistatin-deficient animals increased susceptibility to stroke and worsened prognosis ( i.e., severe neurological score, altered microglial response, impaired astrocyte scar, disrupted BBB, dysregulated angiogenesis, and exacerbated immune infiltration and peripheral response). Interestingly, cortistatin treatment reversed stroke outcomes in animals lacking this neuropeptide, which highlights the key role of cortistatin in regulating the intricate interplay between the nervous and the immune systems, modulating dysregulated cellular and molecular responses from both systems that could impact brain homeostasis. Together, our findings underscore the relevance of identifying the endogenous and therapeutic role of neuro-immune mediators underlying ischemic stroke, and emphasize the critical need to consider multifactorial therapeutic approaches administered at later times and across different ages and phenotypes to extend the current therapeutic window for most patients who do not meet the clinical criteria.
... Ischemic injury induces neuronal loss, resulting in irreversible damage that is erbated by the inflammatory response [37][38][39]. While the majority of neurons are ra lost due to necrosis, neurons continue to undergo apoptosis for weeks following the i (E) Stroke+NWL283-treated mice performed similar to baseline levels at PSD8 and PSD21, with a time dependent reduction in slippage ratios at PSD8 and PSD21, compared to PSD3. ...
... Ischemic injury induces neuronal loss, resulting in irreversible damage that is exacerbated by the inflammatory response [37][38][39]. While the majority of neurons are rapidly lost due to necrosis, neurons continue to undergo apoptosis for weeks following the insult [23,38]. ...
... Ischemic injury induces neuronal loss, resulting in irreversible damage that is exacerbated by the inflammatory response [37][38][39]. While the majority of neurons are rapidly lost due to necrosis, neurons continue to undergo apoptosis for weeks following the insult [23,38]. Pharmacological blockers of apoptotic signalling, such as caspase-3 inhibitors, have been shown to improve cellular and functional outcomes following neural injury. ...
Stroke results in neuronal cell death, which causes long-term disabilities in adults. Treatment options are limited and rely on a narrow window of opportunity. Apoptosis inhibitors demonstrate efficacy in improving neuronal cell survival in animal models of stroke. However, many inhibitors non-specifically target apoptosis pathways and high doses are needed for treatment. We explored the use of a novel caspase-3/7 inhibitor, New World Laboratories (NWL) 283, with a lower IC50 than current caspase-3/7 inhibitors. We performed in vitro and in vivo assays to determine the efficacy of NWL283 in modulating cell death in a preclinical model of stroke. In vitro and in vivo assays show that NWL283 enhances cell survival of neural precursor cells. Delivery of NWL283 following stroke enhances endogenous NPC migration and leads to increased neurogenesis in the stroke-injured cortex. Furthermore, acute NWL283 administration is neuroprotective at the stroke injury site, decreasing neuronal cell death and reducing microglia activation. Coincident with NWL283 delivery for 8 days, stroke-injured mice exhibited improved functional outcomes that persisted following cessation of the drug. Therefore, we propose that NWL283 is a promising therapeutic warranting further investigation to enhance stroke recovery.
... Some research indicates that microglial phagocytosis is responsible for neuronal loss after a stroke [22]. The prevention of delayed neuronal loss and long-term functional deficits is achieved by blocking phagocytic signals, including opsonin milk fat globulin protein E8 or the phagocytic receptor MER proto-oncogene tyrosine kinase (MERTK) [22,23]. Therefore, phagocytic processes may be promising therapeutic targets for preventing delayed neuronal death following stroke. ...
Therapeutic hypothermia (TH) provides neuroprotection. However, the cellular mechanisms underlying the neuroprotective effects of TH are not fully elucidated. Regulation of microglial activation has the potential to treat a variety of nervous system diseases. Transient receptor potential vanilloid 4 (TRPV4), a nonselective cation channel, is activated by temperature stimulus at 27–35 °C. Although it is speculated that TRPV4 is associated with the neuroprotective mechanisms of TH, the role of TRPV4 in the neuroprotective effects of TH is not well understood. In the present study, we investigated whether hypothermia attenuates microglial activation via TRPV4 channels. Cultured microglia were incubated under normothermic (37 °C) or hypothermic (33.5 °C) conditions following lipopolysaccharide (LPS) stimulation. Hypothermic conditions suppressed the expression of pro-inflammatory cytokines, inducible nitric oxide synthase, and the number of phagocytic microglia. AMP-activated protein kinase (AMPK)–NF-κB signaling was inhibited under hypothermic conditions. Furthermore, hypothermia reduced neuronal damage induced by LPS-treated microglial cells. Treatment with TRPV4 antagonist in normothermic culture replicated the suppressive effects of hypothermia on microglial activation and microglia-induced neuronal damage. In contrast, treatment with a TRPV4 agonist in hypothermic culture reversed the suppressive effect of hypothermia. These findings suggest that TH suppresses microglial activation and microglia-induced neuronal damage via the TRPV4-AMPK–NF-κB pathway. Although more validation is needed to consider differences according to age, sex, and specific central nervous system regions, our findings may offer a novel therapeutic approach to complement TH.
... Milk fat globule-epidermal growth factor-factor VIII (MFG-E8), a ligand for the integrins α V β 3 and α V β 5 , acts as an intermediary factor that mediates the recognition and clearance of phagocytes by microglia [13]. In the focal brain ischemia model, MGF-E8 mediates microglial phagocytosis of neurons exposed to phosphatidylserine [14]. MFG-E8 also mediates the phagocytosis of Aβ by microglia in primary glial cell culture, which shows the potential treatment value of MFG-E8 in Alzheimer's disease [15]. ...
... The unique structure of MFG-E8 enables it to act as a tether to attach the debris and apoptotic cells to the phagocytes. In stroke, Aβ stimulation and Brucella abortus infection models, MFG-E8 mediates microglial the phagocytosis of PS-turnover neurons whether they are viable or dead [14,[35][36][37]. Myelin is rich in lipids containing PS. ...
Chronic cerebral hypoperfusion is one of the pathophysiological mechanisms contributing to cognitive decline by causing white matter injury. Microglia phagocytosing myelin debris in a timely manner can promote remyelination and contribute to the repair of white matter. However, milk fat globule-epidermal growth factor-factor 8 (MFG-E8), a microglial phagocytosis-related protein, has not been well studied in hypoperfusion-related cognitive dysfunction. We found that the expression of MFG-E8 was significantly decreased in the brain of mice after bilateral carotid artery stenosis (BCAS). MFG-E8 knockout mice demonstrated more severe BCAS-induced cognitive impairments in the behavioral tests. In addition, we discovered that the deletion of MFG-E8 aggravated white matter damage and the destruction of myelin microstructure through fluorescent staining and electron microscopy. Meanwhile, MFG-E8 overexpression by AAV improved white matter injury and increased the number of mature oligodendrocytes after BCAS. Moreover, in vitro and in vivo experiments showed that MFG-E8 could enhance the phagocytic function of microglia via the α V β 3 /α V β 5 /Rac1 pathway and IGF-1 production to promote the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes. Interestingly, we found that MFG-E8 was mainly derived from astrocytes, not microglia. Our findings suggest that MFG-E8 is a potential therapeutic target for cognitive impairments following cerebral hypoperfusion.
... 174 Surprisingly, sparing these stressed, but viable neurons from clearance has proved to be beneficial, with rats showing reduced motor deficits and overall improved outcome in a brain ischemia/stroke model. 176 The transient upregulation of Mertk in microglia and macrophages at the same time phagoptosis occurred, suggested MERTK may be involved in this process. Consistently, the uptake of stressed neurons was reduced by 60% in Mertk mutants, which showed reduced brain atrophy and improved motor functions. ...
... Taken together, these data suggest that MERTK-mediated phagoptotic cell clearance may constitute a new driver of brain pathology. 176 Therefore, inhibiting MERTK to prevent the engulfment of stressed, yet viable neurons may help the recovery after mild ischemia. Similarly, Fourgeaud et al., showed that ACs clearance through the TAMs not always prevents disease development and point to phagoptotic engulfment of stressed, but live motor neurons by AXL and MERTK as a possible mechanism worsening PD symptoms, and speeding animal death. ...
TYRO3, AXL, and MERTK constitute the TAM family of receptor tyrosine kinases, activated by their ligands GAS6 and PROS1. TAMs are necessary for adult homeostasis in the immune, nervous, reproductive, skeletal, and vascular systems. Among additional cellular functions employed by TAMs, phagocytosis is central for tissue health. TAM receptors are dominant in providing phagocytes with the molecular machinery necessary to engulf diverse targets, including apoptotic cells, myelin debris, and portions of live cells in a phosphatidylserine‐dependent manner. Simultaneously, TAMs drive the release of anti‐inflammatory and tissue repair molecules. Disruption of the TAM‐driven phagocytic pathway has detrimental consequences, resulting in autoimmunity, male infertility, blindness, and disrupted vascular integrity, and which is thought to contribute to neurodegenerative diseases. Although structurally and functionally redundant, the TAM receptors and ligands underlie complex signaling cascades, of which several key aspects are yet to be elucidated. We discuss similarities and differences between TAMs and other phagocytic pathways, highlight future directions and how TAMs can be harnessed therapeutically to modulate phagocytosis.
... Conversely, M2 polarization is known to produce cytokines such as TGF-β, CCL18, and IL-1Ra, which contribute to the reduction of inflammation. Activation of the transcription factor STAT6 can also increase expression of the mannose receptor CD206 and other markers of M2 polarization (Neher et al., 2013). ...
Cerebral ischеmia-rеpеrfusion (CIR) injury is initiated by the generation of reactive oxygen spеciеs (ROS), which leads to thе oxidation of cеllular protеins, DNA, and lipids as an initial еvеnt. Thе rеpеrfusion procеss impairs critical cascadеs that support cеll survival, including mitochondrial biogеnеsis and antioxidant еnzymе activity. Failurе to activatе prosurvival signals may rеsult in incrеasеd nеuronal cеll dеath and еxacеrbation of CIR damagе. Mеlatonin, a hormonе producеd naturally in thе body, has high concеntrations in both thе cеrеbrospinal fluid and thе brain. Howеvеr, mеlatonin production dеclinеs significantly with agе, which may contributе to thе dеvеlopmеnt of agе-rеlatеd nеurological disordеrs duе to rеducеd lеvеls. By activating various signaling pathways, mеlatonin can affect multiple aspects of human health due to its divеrsе range of activitiеs. Thеrеforе, undеrstanding thе undеrlying intracеllular and molеcular mеchanisms is crucial bеforе invеstigating thе nеuroprotеctivе еffеcts of mеlatonin in cеrеbral ischеmia-rеpеrfusion injury.
... Upon central nervous system injury in stroke, phagocytosis is initially executed by microglia. In the peri-infarct area, in ammation induces the reversible exposure of the neuronal eat-me signal phosphatidylserine, leading to phagocytosis of stressed but viable neurons and resulting in brain atrophy and motor dysfunction (97), while in AD microglial clearance of plaques has been suggested to reduce amyloid pathology (56). Our observation that MLN4924 reduced TNF-α-induced microglia phagocytic activity (together with its observed effect on neuronal death upon OGD/RO) underscores a potential therapeutic value of MLN4924 in conditions involving neuroin ammation and ischemic damage. ...
The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is a deNEDDylase controlling ubiquitination activity of cullin-RING-E3 ligases (CRLs) and thus the levels of key cellular proteins. While the CSN and its catalytic subunit CSN5 have been extensively studied in cancer, its role in inflammatory and neurological diseases is less understood. Following verification that CSN5 is expressed in mouse and human brain, here we studied the role of the CSN in neuroinflammation and ischemic neuronal damage employing models of relevant brain-resident cell types, an ex vivo organotypic brain slice culture model, and the CRL NEDDylation state-modifying drugs MLN4924 and CSN5i-3, which mimic and inhibit, respectively, CSN5 deNEDDylase activity. Unbiased mass spectrometry-based proteomics revealed that MLN4924 and CSN5i-3 substantially alter the microglial proteome, including inflammation-related proteins. Applying these drugs, mimicking microglial and endothelial inflammation as well as ischemic neuronal stress by TNF-α and oxygen-glucose-deprivation/reoxygenation (OGD/RO) treatment, we could link CSN5/CSN-mediated cullin deNEDDylation to reduction of microglial inflammation, attenuated cerebral endothelial inflammation, improved barrier integrity, as well as protection from ischemia stress-induced neuronal cell death. Specifically, MLN4924 reduced phagocytic activity, motility, and inflammatory cytokine expression of BV2 and primary microglial cells, and this was linked to inhibition of inflammation-induced NF-kB, MAPK, and Akt signaling. Inversely, Csn5 knockdown and CSN5i-3 increased NF-kB signaling. Moreover, MLN4924 abrogated TNF-a-induced NF-kB and MAPK signaling in cerebral microvascular endothelial cells (hCMECs) and rescued hCMEC monolayers from OGD/RO-triggered barrier leakage via restoring tight junctions, while CSN5i-3 exacerbated permeability. In an ex vivo organotypic brain slice model of ischemia/reperfusion stress, MLN4924 protected from neuronal death, while CSN5i-3 impaired neuronal survival. Neuronal damage was attributable to microglial activation and inflammatory cytokines, as indicated by microglial shape tracking and TNF-a-blocking experiments. Our results indicate a protective role of the CSN in neuroinflammation via several brain-resident cell types involved in ischemic brain disease and implicate CSN activity-mimicking deNEDDylating drugs as potential therapeutics.
... The combination of opsonin, such as growth arrest-specific protein 6 (GAS6), galectin-3 (Gal-3), and Tubby with "eat me" signal on the surface of neurons can activate the microglia surface receptor c-mer tyrosine kinase (MerTK) [218,219]. The upregulation of MFG-E8 and MerTK has been reported to be delayed by 2 to 3 days after focal cerebral ischemia in an animal model [220], which may be consistent with the resolution of inflammation. Thus, the specific binding of phosphatidylserines to opsonins and the expression of their receptors results in the detection and phagocytosis of signal-exposed neurons, a process that contributes to inflammatory response [193]. ...
Stroke causes varying degrees of neurological deficits, leading to corresponding dysfunctions. There are different therapeutic principles for each stage of pathological development. Neuroprotection is the main treatment in the acute phase, and functional recovery becomes primary in the subacute and chronic phases. Neuroplasticity is considered the basis of functional restoration and neurological rehabilitation after stroke, including the remodeling of dendrites and dendritic spines, axonal sprouting, myelin regeneration, synapse shaping, and neurogenesis. Spatiotemporal development affects the spontaneous rewiring of neural circuits and brain networks. Microglia are resident immune cells in the brain that contribute to homeostasis under physiological conditions. Microglia are activated immediately after stroke, and phenotypic polarization changes and phagocytic function are crucial for regulating focal and global brain inflammation and neurological recovery. We have previously shown that the development of neuroplasticity is spatiotemporally consistent with microglial activation, suggesting that microglia may have a profound impact on neuroplasticity after stroke and may be a key therapeutic target for post-stroke rehabilitation. In this review, we explore the impact of neuroplasticity on post-stroke restoration as well as the functions and mechanisms of microglial activation, polarization, and phagocytosis. This is followed by a summary of microglia-targeted rehabilitative interventions that influence neuroplasticity and promote stroke recovery.
