Microglia and Monocytes/Macrophages Polarization Reveal Novel Therapeutic Mechanism against Stroke

Kanazawa, Masato; Ninomiya, Itaru; Hatakeyama, Masahiro; Takahashi, Tetsuya; Shimohata, Takayoshi

doi:10.3390/ijms18102135

Cited by 337 publications

(253 citation statements)

References 129 publications

(177 reference statements)

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“…In macrophages, the two different subsets-M1 and M2-express different MMPs [95]. MMP-9-which depicts pro-inflammatory roles in BBB opening and cytokine activation-is secreted by M2 microglia and involved as a remodeling factor during repair [96,97]. Kohkha et al further suggest that MMPs-apart from being differentially expressed in M1 and M2 subsets-might also contribute to phenotype polarization by regulating cytokine and growth factor availability [15].…”

Section: Mmps and Microgliamentioning

confidence: 99%

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

Muri

Leppert

Grandgirard

et al. 2019

Cell. Mol. Life Sci.

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Metalloproteinases-such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs)-are involved in various diseases of the nervous system but also contribute to nervous system development, synaptic plasticity and neuroregeneration upon injury. MMPs and ADAMs proteolytically cleave many substrates including extracellular matrix components but also signaling molecules and receptors. During neuroinfectious disease with associated neuroinflammation, MMPs and ADAMs regulate blood-brain barrier breakdown, bacterial invasion, neutrophil infiltration and cytokine signaling. Specific and broad-spectrum inhibitors for MMPs and ADAMs have experimentally been shown to decrease neuroinflammation and brain damage in diseases with excessive neuroinflammation as a common denominator, such as pneumococcal meningitis and multiple sclerosis, thereby improving the disease outcome. Timing of metalloproteinase inhibition appears to be critical to effectively target the cascade of pathophysiological processes leading to brain damage without inhibiting the neuroregenerative effects of metalloproteinases. As the critical role of metalloproteinases in neuronal repair mechanisms and regeneration was only lately recognized, the original idea of chronic MMP inhibition needs to be conceptually revised. Recently accumulated research urges for a second chance of metalloproteinase inhibitors, which-when correctly applied and dosed-harbor the potential to improve the outcome of different neuroinflammatory diseases.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Section: Mmps and Microgliamentioning

confidence: 99%

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

Muri

Leppert

Grandgirard

et al. 2019

Cell. Mol. Life Sci.

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“…One of the potential therapeutic approaches based on aforementioned findings could be to use M2‐like microglial cell therapy for stroke. The M2‐like microglia and monocytes/monocytes secrete protective remodeling factors, thus prompting neuronal network recovery via tissue/vascular remodeling; however, future translational studies are required …”

Section: Sex Differences In Microglia‐induced Inflammationmentioning

confidence: 99%

“…The M2-like microglia and monocytes/monocytes secrete protective remodeling factors, thus prompting neuronal network recovery via tissue/vascular remodeling; however, future translational studies are required. 65 A more recent area of neuroinflammatory research has been the role of extracellular vesicles, which are small nano-to-micrometer vesicles involved in cell-to-cell communication. It is understood that extracellular vesicles (EVs) play a critical role in coordinating communication between microglia, neurons, and astrocytes.…”

Section: S E X D Ifferen Ce S In Mi Crog Lia-induced Infl Ammationmentioning

confidence: 99%

Sexually dimorphic microglia and ischemic stroke

et al. 2019

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Ischemic stroke kills more women compared with men thus emphasizing a significant sexual dimorphism in ischemic pathophysiological outcomes. However, the mechanisms behind this sexual dimorphism are yet to be fully understood. It is well established that cerebral ischemia activates a variety of inflammatory cascades and that microglia are the primary immune cells of the brain. After ischemic injury, microglia are activated and play a crucial role in progression and resolution of the neuroinflammatory response. In recent years, research has focused on the role that microglia play in this sexual dimorphism that exists in the response to central nervous system (CNS) injury. Evidence suggests that the molecular mechanisms leading to microglial activation and polarization of phenotypes may be influenced by sex, therefore causing a difference in the pro/anti‐inflammatory responses after CNS injury. Here, we review advances highlighting that sex differences in microglia are an important factor in the inflammatory responses that are seen after ischemic injury. We discuss the main differences between microglia in the healthy and diseased developing, adult, and aging brain. We also focus on the dimorphism that exists between males and females in microglial‐induced inflammation and energy metabolism after CNS injury. Finally, we describe how all of the current research and literature regarding sex differences in microglia contribute to the differences in poststroke responses between males and females.

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“…The lone FDA-approved stroke medication is rtPA, a thrombolytic agent (Moretti, Ferrari, & Villa, 2015). Due to heightened risk of cerebral haemorrhage, rtPA can only be applied during the first 4.5 h after stroke onset, so only about 4% of stroke victims receive rtPA (Kanazawa, Ninomiya, Hatakeyama, Takahashi, & Shimohata, 2017). Therapeutic hypothermia has proven safe and efficacious for stroke treatment in many but not all Phase I and II clinical trials (Tahir & Pabaney, 2016).…”

Section: Injury Mechanisms and Treatment Challenges Of Strokementioning

confidence: 99%

“…The resident immune cells of the brain, activated microglia, assume pro-inflammatory M1 or anti-inflammatory M2 polarities (Kanazawa et al, 2017). Damaged neurons release ATP and UTP, which act on purine receptors to induce microglial differentiation to the M1 phenotype (Iadecola & Anrather, 2011).…”

Section: Microglial Polarity: Neuroprotection Vs Neuroinflammmationmentioning

confidence: 99%

Ischaemic and hypoxic conditioning: potential for protection of vital organs

Sprick

Mallet

Przyklenk

et al. 2019

Experimental Physiology

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New Findings What is the topic of this review?Remote ischaemic preconditioning (RIPC) and hypoxic preconditioning as novel therapeutic approaches for cardiac and neuroprotection. What advances does it highlight?There is improved understanding of mechanisms and signalling pathways associated with ischaemic and hypoxic preconditioning, and potential pitfalls with application of these therapies to clinical trials have been identified. Novel adaptations of preconditioning paradigms have also been developed, including intermittent hypoxia training, RIPC training and RIPC–exercise, extending their utility to chronic settings. Abstract Myocardial infarction and stroke remain leading causes of death worldwide, despite extensive resources directed towards developing effective treatments. In this Symposium Report we highlight the potential applications of intermittent ischaemic and hypoxic conditioning protocols to combat the deleterious consequences of heart and brain ischaemia. Insights into mechanisms underlying the protective effects of intermittent hypoxia training are discussed, including the activation of hypoxia‐inducible factor‐1 and Nrf2 transcription factors, synthesis of antioxidant and ATP‐generating enzymes, and a shift in microglia from pro‐ to anti‐inflammatory phenotypes. Although there is little argument regarding the efficacy of remote ischaemic preconditioning (RIPC) in pre‐clinical models, this strategy has not consistently translated into the clinical arena. This lack of translation may be related to the patient populations targeted thus far, and the anaesthetic regimen used in two of the major RIPC clinical trials. Additionally, we do not fully understand the mechanism through which RIPC protects the vital organs, and co‐morbidities (e.g. hypercholesterolemia, diabetes) may interfere with its efficacy. Finally, novel adaptations have been made to extend RIPC to more chronic settings. One adaptation is RIPC–exercise (RIPC‐X), an innovative paradigm that applies cyclical RIPC to blood flow restriction exercise (BFRE). Recent findings suggest that this novel exercise modality attenuates the exaggerated haemodynamic responses that may limit the use of conventional BFRE in some clinical settings. Collectively, intermittent ischaemic and hypoxic conditioning paradigms remain an exciting frontier for the protection against ischaemic injuries.

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Microglia and Monocytes/Macrophages Polarization Reveal Novel Therapeutic Mechanism against Stroke

Cited by 337 publications

References 129 publications

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

Sexually dimorphic microglia and ischemic stroke

Ischaemic and hypoxic conditioning: potential for protection of vital organs

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