TMEM16F inhibition limits pain-associated behavior and improves motor function by promoting microglia M2 polarization in mice

Zhao, Jing; Gao, Quan-You

doi:10.1016/j.bbrc.2019.07.070

Cited by 10 publications

(7 citation statements)

References 39 publications

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“…It has been reported that expression of TMEM16F is significantly higher in macrophages, where it supports phagocytic activity and cell death (57). Recent studies find that TMEM16F plays an important role in regulating spinal microglia function in neuropathic pain states (58) and spinal cord injury (59). Likely due to a different disease model and the microglia accounting for only 20% of brain tissue, TMEM16F was mainly expressed on the neuronal membrane instead of the microglia in our study after MCAO/R.…”

Section: Discussionmentioning

confidence: 39%

TMEM16F Aggravates Neuronal Loss by Mediating Microglial Phagocytosis of Neurons in a Rat Experimental Cerebral Ischemia and Reperfusion Model

Zhang

et al. 2020

Front. Immunol.

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Cerebral ischemia is a severe, acute condition, normally caused by cerebrovascular disease, and results in high rates of disability, and death. Phagoptosis is a newly recognized form of cell death caused by phagocytosis of viable cells, and has been reported to contribute to neuronal loss in brain tissue after ischemic stroke. Previous data indicated that exposure of phosphatidylserine to viable neurons could induce microglial phagocytosis of such neurons. Phosphatidylserine can be reversibly exposed to viable cells as a result of a calcium-activated phospholipid scramblase named TMEM16F. TMEM16F-mediated phospholipid scrambling on platelet membranes is critical for hemostasis and thrombosis, which plays an important role in Scott syndrome and has been confirmed by much research. However, few studies have investigated the association between TMEM16F and phagocytosis in ischemic stroke. In this study, a middle-cerebral-artery occlusion/reperfusion (MCAO/R) model was used in adult male Sprague-Dawley rats in vivo, and cultured neurons were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to simulate cerebral ischemia-reperfusion (I/R) injury in vitro. We found that the protein level of TMEM16F was significantly increased at 12 h after I-R injury both in vivo and in vitro, and reversible phosphatidylserine exposure was confirmed in neurons undergoing I/R injury in vitro. Additionally, we constructed a LV-TMEM16F-RNAi transfection system to suppress the expression of TMEM16F during and after cerebral ischemia. As a result, TMEM16F knockdown alleviated motor function injury and decreased the microglial phagocytosis of viable neurons in the penumbra through inhibiting the "eat-me" signal phosphatidylserine. Our data indicate that reducing neuronal phosphatidylserine-exposure via deficiency of TMEM16F blocks phagocytosis of neurons and rescues stressed-but-still-viable neurons in the penumbra, which may contribute to reducing infarct volume and improving functional recovering.

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Section: Discussionmentioning

confidence: 39%

TMEM16F Aggravates Neuronal Loss by Mediating Microglial Phagocytosis of Neurons in a Rat Experimental Cerebral Ischemia and Reperfusion Model

Zhang

et al. 2020

Front. Immunol.

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“…For example, microglia respond differently to diverse pathological stimuli and change their behavior over the evolution of any given pathology [52] in relation to different phagocytic activities [53] and transcriptional profiles [47,54] in different brain regions and at different ages. Notably, polarization into the “classically activated” M1 phenotype can be blocked in microglia after spinal cord injury by deletion of TMEM16F, a protein that functions as a Ca 2+ -dependent ion channel and phospholipid scramblase [55], which provides a new tool to study microglial function. This protein has also been shown to be essential for the development of neuropathic pain in mice [56].…”

Section: Overview Of the Neurobiology Of Microgliamentioning

confidence: 99%

What Do Microglia Really Do in Healthy Adult Brain?

Augusto-Oliveira

Arrifano

Lopes-Araújo

et al. 2019

Cells

116

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Microglia originate from yolk sac-primitive macrophages and auto-proliferate into adulthood without replacement by bone marrow-derived circulating cells. In inflammation, stroke, aging, or infection, microglia have been shown to contribute to brain pathology in both deleterious and beneficial ways, which have been studied extensively. However, less is known about their role in the healthy adult brain. Astrocytes and oligodendrocytes are widely accepted to strongly contribute to the maintenance of brain homeostasis and to modulate neuronal function. On the other hand, contribution of microglia to cognition and behavior is only beginning to be understood. The ability to probe their function has become possible using microglial depletion assays and conditional mutants. Studies have shown that the absence of microglia results in cognitive and learning deficits in rodents during development, but this effect is less pronounced in adults. However, evidence suggests that microglia play a role in cognition and learning in adulthood and, at a cellular level, may modulate adult neurogenesis. This review presents the case for repositioning microglia as key contributors to the maintenance of homeostasis and cognitive processes in the healthy adult brain, in addition to their classical role as sentinels coordinating the neuroinflammatory response to tissue damage and disease.

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“…Ano6 -/mouse models have implicated TMEM16F in many other processes including pain behaviour, mucus production, bone mineralisation and preventing immune cell overactivation. [41][42][43][44] TMEM16F is also implicated in entry of enveloped viruses, including Ebola and HIV. 45,46 Due to the small number of Scott Syndrome patients it is not known if TMEM16F plays similar roles in human physiology.…”

Section: Animal Models Of Scott Syndromementioning

confidence: 99%

Gene of the issue: ANO6 and Scott Syndrome

Millington‐Burgess

Harper

2019

Platelets

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Scott Syndrome is a very rare inhibited bleeding disorder characterised by an isolated deficit in procoagulant activity in platelets and other blood cells, caused by a lack of phosphatidylserine (PS) exposure following activation. 1,2 It results from mutations in ANO6, which encodes the phospholipid scramblase protein, TMEM16F. 3 Platelet PS exposure in coagulation Negatively charged phospholipidsparticularly PS, but also phosphatidylethanolamine (PE) facilitate Ca 2+-dependent binding of the γ-carboxyglutamate (Gla) domains of vitamin Kdependent coagulation factors (factors II [prothrombin], VII, IX and X) to phospholipid membranes. 4 This promotes the formation of the tenase and prothrombinase complexes on PS-exposing platelets. PS-exposing platelets also enhance the activities of these complexes by nearly 1000-fold. 5 Platelet PS exposure therefore plays a central role in coagulation.

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TMEM16F inhibition limits pain-associated behavior and improves motor function by promoting microglia M2 polarization in mice

Cited by 10 publications

References 39 publications

TMEM16F Aggravates Neuronal Loss by Mediating Microglial Phagocytosis of Neurons in a Rat Experimental Cerebral Ischemia and Reperfusion Model

TMEM16F Aggravates Neuronal Loss by Mediating Microglial Phagocytosis of Neurons in a Rat Experimental Cerebral Ischemia and Reperfusion Model

What Do Microglia Really Do in Healthy Adult Brain?

Gene of the issue: ANO6 and Scott Syndrome

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