Macrophage-derived osteopontin induces reactive astrocyte polarization and promotes re-establishment of the blood brain barrier after ischemic stroke

Gliem, Michael; Krammes, Kristina; Liaw, Lucy; Rooijen, Nico van; Hartung, Hans‐Peter; Jander, Sebastian

doi:10.1002/glia.22885

Cited by 104 publications

(79 citation statements)

References 42 publications

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“…However, the full extent and mechanisms of IFN signaling in IPCmediated protection remain to be explored. The cellular source of IFN-β in the postischemic brain is unknown, but there are several possible sources such as peripheral macrophages [53,54] and astrocytes [55][56][57][58]. Published studies also suggest neurons [59] are capable of releasing IFN-β under specific conditions.…”

Section: Molecular Mediators Of Preconditioningmentioning

confidence: 99%

“…Microglia express multiple complement receptors, including CR3, and this signaling pathway greatly influences phagocytic function of microglia [112,113]. There is also evidence that infiltrating immune cells may influence astrocyte activation and behavior [58], suggesting astrocytes may be an important mediator between resident and peripheral immune cells and neurons. Astrocytes also produce many regulatory factors that may provide negative feedback to microglia, helping to modulate microglial activation states.…”

Section: Astrocytesmentioning

confidence: 99%

“…Some evidence suggests that peripheral macrophages play a key role in stroke pathophysiology [58,76]; however, their role in IPC is unknown. Macrophages infiltrate the infarct border zone within hours of stroke onset and they undergo differentiation from a proinflammatory to a noninflammatory profile, which facilitates tissue repair [74,152].…”

Section: Peripheral Immune Cellsmentioning

confidence: 99%

“…Macrophages infiltrate the infarct border zone within hours of stroke onset and they undergo differentiation from a proinflammatory to a noninflammatory profile, which facilitates tissue repair [74,152]. Macrophages are the primary producers of osteopontin, which may have neuroprotective and repair-promoting effects in CNS injury, including ischemia [58]. Recently published evidence suggests that osteopontin is critical for the polarization of astrocytes and establishment of an astrocytic barrier (glial scar) in the outer part of the ischemic core [58], suggesting another layer of interaction between immune cells and astrocytes.…”

Section: Peripheral Immune Cellsmentioning

confidence: 99%

“…Recently published evidence suggests that osteopontin is critical for the polarization of astrocytes and establishment of an astrocytic barrier (glial scar) in the outer part of the ischemic core [58], suggesting another layer of interaction between immune cells and astrocytes. Furthermore, this study implicated osteopontin stimulation of astrocytes in the reestablishment of the BBB after ischemia [58].…”

Section: Peripheral Immune Cellsmentioning

confidence: 99%

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Correction to: Neuroimmune Response in Ischemic Preconditioning

McDonough

Weinstein

2018

Neurotherapeutics

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Ischemic preconditioning (IPC) is a robust neuroprotective phenomenon in which a brief period of cerebral ischemia confers transient tolerance to subsequent ischemic challenge. Research on IPC has implicated cellular, molecular, and systemic elements of the immune response in this phenomenon. Potent molecular mediators of IPC include innate immune signaling pathways such as Tolllike receptors and type 1 interferons. Brain ischemia results in release of pro-and anti-inflammatory cytokines and chemokines that orchestrate the neuroinflammatory response, resolution of inflammation, and transition to neurological recovery and regeneration. Cellular mediators of IPC include microglia, the resident central nervous system immune cells, astrocytes, and neurons. All of these cell types engage in cross-talk with each other using a multitude of signaling pathways that modulate activation/ suppression of each of the other cell types in response to ischemia. As the postischemic neuroimmune response evolves over time there is a shift in function toward provision of trophic support and neuroprotection. Peripheral immune cells infiltrate the central nervous system en masse after stroke and are largely detrimental, with a few subtypes having beneficial, protective effects, though the role of these immune cells in IPC is largely unknown. The role of neural progenitor cells in IPC-mediated neuroprotection is another active area of investigation as is the role of microglial proliferation in this setting. A mechanistic understanding of these molecular and cellular mediators of IPC may not only facilitate more effective direct application of IPC to specific clinical scenarios, but also, more broadly, reveal novel targets for therapeutic intervention in stroke. Keywords PreconditioningIschemic preconditioning (IPC) is an experimental phenomenon in which a brief period of ischemia confers robust neuroprotection against subsequent ischemic events [1-3]. It is important to note that preconditioning does not reduce the incidence of stroke, but rather ameliorates the pathophysiologic response to cerebral ischemia and results in a smaller infarct volume and improved poststroke recovery [4][5][6]. Clinical studies suggest that patients with stroke who suffered a recent prior transient ischemic attack have better outcomes than those who did not, implying that a human correlate to experimental IPC exists [7,8]. Elucidating the mechanisms of IPC is considered a critical challenge in stroke research [9,10]. Recent literature has implicated innate immune pathways, including Toll-like receptors (TLRs) [11,12] and type 1 interferon (IFN) signaling [5,11,13] in IPC-mediated protection.Due to a technical error in the production process, the earlier version of this article contained numerous errors in the reference numbering. We are reprinting the entire article in the correction for readabilityThe online version of the original article can be found at https://doi

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Section: Molecular Mediators Of Preconditioningmentioning

confidence: 99%

Section: Astrocytesmentioning

confidence: 99%

Section: Peripheral Immune Cellsmentioning

confidence: 99%

Section: Peripheral Immune Cellsmentioning

confidence: 99%

Section: Peripheral Immune Cellsmentioning

confidence: 99%

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Correction to: Neuroimmune Response in Ischemic Preconditioning

McDonough

Weinstein

2018

Neurotherapeutics

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Critical roles of astrocytic‐CCL2‐dependent monocyte infiltration in a DJ‐1 knockout mouse model of delayed brain repair

Choi

Yang

Gaire

et al. 2020

Glia

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Monocyte‐derived macrophages play a role in the repair of the injured brain. We previously reported that a deficiency of the Parkinson's disease (PD)‐associated gene DJ‐1 delays repair of brain injury produced by stereotaxic injection of ATP, a component of damage‐associated molecular patterns. Here, we show that a DJ‐1 deficiency attenuates monocyte infiltration into the damaged brain owing to a decrease in C‐C motif chemokine ligand 2 (CCL2) expression in astrocytes. Like DJ‐1‐knockout (KO) mice, CCL2 receptor (CCR2)‐KO mice showed defects in monocyte infiltration and delayed recovery of brain injury, as determined by 9.4 T magnetic resonance imaging analysis and immunostaining for tyrosine hydroxylase and glial fibrillary acid protein. Notably, transcriptome analyses showed that genes related to regeneration and synapse formation were similarly downregulated in injured brains of DJ‐1‐KO and CCR2‐KO mice compared with the injured wild‐type brain. These results indicate that defective astrogliosis in DJ‐1‐KO mice is associated with decreased CCL2 expression and attenuated monocyte infiltration, resulting in delayed repair of brain injury. Thus, delayed repair of brain injury could contribute to the development of PD.Main PointsA DJ‐1 deficiency attenuates infiltration of monocytes owing to a decrease in CCL2 expression in astrocytes, which in turn led to delay in repair of brain injury.

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Astroglial N‐myc downstream‐regulated gene 2 protects the brain from cerebral edema induced by stroke

Guo

Yin

et al. 2020

Glia

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Brain edema is a grave complication of brain ischemia and is the main cause of herniation and death. Although astrocytic swelling is the main contributor to cytotoxic edema, the molecular mechanism involved in this process remains elusive. N-myc downstream-regulated gene 2 (NDRG2), a well-studied tumor suppressor gene, is mainly expressed in astrocytes in mammalian brains. Here, we found that NDRG2 deficiency leads to worsened cerebral edema, imbalanced Na + transfer, and astrocyte swelling after ischemia. We also found that NDRG2 deletion in astrocytes dramatically changed the expression and distribution of aquaporin-4 and Na +-K +-ATPase β1, which are strongly associated with cell polarity, in the ischemic brain. Brain edema and astrocyte swelling were significantly alleviated by rescuing the expression of astrocytic Na +-K +-ATPase β1 in NDRG2-knockout mouse brains. In addition, the upregulation of astrocytic NDRG2 by lentiviral constructs notably attenuated brain edema, astrocytic swelling, and blood-brain barrier destruction. Our results indicate a particular role of NDRG2 in maintaining astrocytic polarization to facilitate Na + and water transfer balance and to protect the brain from ischemic edema. These findings provide insight into NDRG2 as a therapeutic target in cerebral edema. Hang Guo, Anqi Yin, and Yulong Ma contributed equally to this study.

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Macrophage-derived osteopontin induces reactive astrocyte polarization and promotes re-establishment of the blood brain barrier after ischemic stroke

Cited by 104 publications

References 42 publications

Correction to: Neuroimmune Response in Ischemic Preconditioning

Correction to: Neuroimmune Response in Ischemic Preconditioning

Critical roles of astrocytic‐CCL2‐dependent monocyte infiltration in a DJ‐1 knockout mouse model of delayed brain repair

Astroglial N‐myc downstream‐regulated gene 2 protects the brain from cerebral edema induced by stroke

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