Phagocytosis executes delayed neuronal death after focal brain ischemia

Neher, Jonas J.; Emmrich, J; Fricker, Michael; Mander, Palwinder K.; Théry, Clotilde; Brown, Guy C.

doi:10.1073/pnas.1308679110

Cited by 279 publications

(313 citation statements)

References 58 publications

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“…PS exposure is not itself toxic to neurons, but rather marks the neuron for selective removal by microglia. If activated microglia are present, this results in phagocytosis of the PS‐exposed neurons 26, 27, 28, 32. In line with this thinking, our data suggest that LPC C26:0, in particular at low dose (15 µM), does not cause significant neuronal toxicity in culture despite leading to PS exposure.…”

Section: Discussionsupporting

confidence: 83%

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Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

Gong

Sasidharan

Laheji

et al. 2017

Annals of Neurology

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ObjectiveMutations in ABCD1 cause the neurodegenerative disease, adrenoleukodystrophy, which manifests as the spinal cord axonopathy adrenomyeloneuropathy (AMN) in nearly all males surviving into adulthood. Microglial dysfunction has long been implicated in pathogenesis of brain disease, but its role in the spinal cord is unclear.MethodsWe assessed spinal cord microglia in humans and mice with AMN and investigated the role of ABCD1 in microglial activity toward neuronal phagocytosis in cell culture. Because mutations in ABCD1 lead to incorporation of very‐long‐chain fatty acids into phospholipids, we separately examined the effects of lysophosphatidylcholine (LPC) upon microglia.ResultsWithin the spinal cord of humans and mice with AMN, upregulation of several phagocytosis‐related markers, such as MFGE8 and TREM2, precedes complement activation and synapse loss. Unexpectedly, this occurs in the absence of overt inflammation. LPC C26:0 added to ABCD1‐deficient microglia in culture further enhances MFGE8 expression, aggravates phagocytosis, and leads to neuronal injury. Furthermore, exposure to a MFGE8‐blocking antibody reduces phagocytic activity.InterpretationSpinal cord microglia lacking ABCD1 are primed for phagocytosis, affecting neurons within an altered metabolic milieu. Blocking phagocytosis or specific phagocytic receptors may alleviate synapse loss and axonal degeneration. Ann Neurol 2017;82:813–827

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Section: Discussionsupporting

confidence: 83%

“…Both the literature26, 27, 28 and our own experiments confirm that phagocytosis of neurons and axons with exposed PS can be mediated by MFGE8. In general, two prerequisites are necessary for microglial engulfment of live neurons and axons.…”

Section: Discussionsupporting

confidence: 78%

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

Gong

Sasidharan

Laheji

et al. 2017

Annals of Neurology

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“…CX 3 CR1-expressing mononuclear phagocytes migrate toward the dying neurons that release CX 3 CL1 [143][144][145]. M2 macrophages that highly express CX 3 CR1 are considered to be a major subset that engages in phagocytosis as shown in in vitro neuronmicroglia co-culture and organotypic slice culture [146,147]. However, CD68, a marker of phagocytic activity, was shown to be inversely correlated with other M2 markers during stroke injury development [112], casting uncertainty on the relationship between M2 marker expression and phagocytic function.…”

Section: Inflammation Versus Resolutionmentioning

confidence: 99%

Microglia and Monocyte-Derived Macrophages in Stroke

2016

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Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.

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“…Phagocytosis is the primary mechanism used to remove pathogens and cell debris. Mer deficiency inhibits phagocytosis in focal brain ischaemia and retinal pigment epithelial (RPE) cells [56,59]. Mer receptors were upregulated in activated microglia 3 days after injection of the vasoconstrictor endothelin-1 in a focal brain ischaemia rat model.…”

Section: Tam Signalling In Degeneration Following Central or Periphermentioning

confidence: 99%

“…Mer receptors were upregulated in activated microglia 3 days after injection of the vasoconstrictor endothelin-1 in a focal brain ischaemia rat model. Knockdown of Mer using Mer mutant mice inhibited microglial engulfment of neurons after ischaemia and produced a pronounced reduction of neuronal loss that strongly reduced brain atrophy and improved motor function in MerTK mutant rats [59]. However, the phagocytosis of the photoreceptor outer segment is critical to the normal functioning of the retina.…”

Section: Tam Signalling In Degeneration Following Central or Periphermentioning

confidence: 99%

The Role of the TAM Family of Receptor Tyrosine Kinases in Neural Development and Disorders

Zhang¹,

Qi²

2018

Neuropsychiatry

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Tyrosine kinase receptor 3 (Tyro3), Axl, and Mer constitute the TAM family of receptor tyrosine kinases. These receptor tyrosine kinases are characterized by a conserved sequence within the kinase domain and adhesion molecule-like extracellular domains. The TAM family and their shared ligands, growth arrest-specific gene-6 (Gas6) and protein S, are differentially expressed in the developing and adult nervous systems. The TAM family regulates normal cellular processes and plays an important role in nervous system development and diseases, including cell proliferation/survival, cell adhesion and migration, neuronal differentiation, cell apoptosis, myelination, degeneration, and immune regulation. This review summarizes the developing expression of the TAM family and ligands and their function in neural development and nervous system diseases. Further research will be necessary to fully elucidate the function of the TAM family and to evaluate the clinical implications of TAM family expression and activation in nervous system diseases.

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Phagocytosis executes delayed neuronal death after focal brain ischemia

Cited by 279 publications

References 58 publications

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

Microglia and Monocyte-Derived Macrophages in Stroke

The Role of the TAM Family of Receptor Tyrosine Kinases in Neural Development and Disorders

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