MFGE8 does not orchestrate clearance of apoptotic neurons in a mouse model of Parkinson's disease

Kinugawa, Kiyoka; Monnet, Yann; Lü, Lixia; Bekaert, Alain; Théry, Clotilde; Mallat, Ziad; Hirsch, Étienne C.; Hunot, Stéphane

doi:10.1016/j.nbd.2012.11.010

Cited by 10 publications

(8 citation statements)

References 34 publications

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“…Interestingly, the downregulation of Mfge8 after 24 hr was detected at the time point when microglia show the strongest activation. Although this study does not show whether microglia are the source of Mfge8, recent reports have shown that microglia and/or astrocytes express Mfge8 depending on the model analyzed (Neniskyte and Brown, 2013;Kranich et al, 2010;Kinugawa et al, 2013). In the present study, we have analyzed the expression of Mfge8 in microglia under different activation paradigms.…”

Section: Discussionmentioning

confidence: 73%

TGFβ1 increases microglia-mediated engulfment of apoptotic cells via upregulation of the milk fat globule-EGF factor 8

Spittau

Rilka

Steinfath

et al. 2014

Glia

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Milk fat globule-epidermal growth factor-factor 8 (Mfge8) has been described as an essential molecule during microglia-mediated clearance of apoptotic cells via binding to phosphatidylserine residues and subsequent phagocytosis. Impaired uptake of apoptotic cells by microglia results in prolonged inflammatory responses and damage of healthy cells. Although the mechanisms of Mfge8-mediated engulfment of apoptotic cells are well understood, endogenous or exogenous factors that regulate Mfge8 expression remain elusive. Here, we describe that TGFβ1 increases the expression of Mfge8 and enhances the engulfment of apoptotic cells by primary mouse microglia in a Mfge8-dependent manner. Further, apoptotic cells are capable of increasing microglial TGFβ expression and release and shift the microglia phenotype toward alternative activation. Moreover, we provide evidence that Mfge8 expression is differentially regulated in microglia after classical and alternative activation and that Mfge8 is not able to exert direct antiinflammatory effects on LPS-treated primary microglia. Together, these results underline the importance of TGFβ1 as a regulatory factor for microglia and suggest that increased TGFβ1 expression in models of neurodegeneration might be involved in clearance of apoptotic cells via regulation of Mfge8 expression.

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Section: Discussionmentioning

confidence: 73%

TGFβ1 increases microglia-mediated engulfment of apoptotic cells via upregulation of the milk fat globule-EGF factor 8

Spittau

Rilka

Steinfath

et al. 2014

Glia

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“…), a key oxidant‐producing enzyme during inflammation, milk fat globule‐EGF factor 8 (Kinugawa et al . ), a factor involved in phagocytic recognition, and heme oxygenase‐1 (Schipper et al . ), an antioxidant enzyme involved in the regulation of the inflammatory process, were reported specifically in astrocytes in the parkinsonian brain.…”

Section: Inflammationmentioning

confidence: 99%

“…In contrast to microglial cells, the activated status of astrocytes is more controversial in brains of PD patients, since some studies detect astrogliosis through the increased expression of GFAP (Glial Fibrillary Acidic Protein) (Mythri et al 2011;Lastres-Becker et al 2012) or ICAM-1 (Miklossy et al 2006) while others did not (Mirza et al 1999;Tong et al 2015). However, whether astrogliosis was triggered or not, inflammatory events seemed to affect astrocytes since increased levels of myeloperoxidase (Choi et al 2005a), a key oxidant-producing enzyme during inflammation, milk fat globule-EGF factor 8 (Kinugawa et al 2013), a factor involved in phagocytic recognition, and heme oxygenase-1 (Schipper et al 2009), an antioxidant enzyme involved in the regulation of the inflammatory process, were reported specifically in astrocytes in the parkinsonian brain. Importantly, infiltration of peripheral immune cells could also participate in the neuroinflammatory response in PD since lymphocyte function-associated antigen 1-positive leukocytes (Miklossy et al 2006), CD8-positive and CD4-positive T cells (Brochard et al 2009) were found in the SN of PD patients.…”

Section: Inflammationmentioning

confidence: 99%

Molecular changes in the postmortem parkinsonian brain

Toulorge

Schapira²,

Hajj

2016

Journal of Neurochemistry

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Parkinson disease (PD) is the second most common neurodegenerative disease after Alzheimer disease. Although PD has a relatively narrow clinical phenotype, it has become clear that its etiological basis is broad. Post-mortem brain analysis, despite its limitations, has provided invaluable insights into relevant pathogenic pathways including mitochondrial dysfunction, oxidative stress and protein homeostasis dysregulation. Identification of the genetic causes of PD followed the discovery of these abnormalities, and reinforced the importance of the biochemical defects identified post-mortem. Recent genetic studies have highlighted the mitochondrial and lysosomal areas of cell function as particularly significant in mediating the neurodegeneration of PD. Thus the careful analysis of post-mortem PD brain biochemistry remains a crucial component of research, and one that offers considerable opportunity to pursue etiological factors either by 'reverse biochemistry' i.e. from defective pathway to mutant gene, or by the complex interplay between pathways e.g. mitochondrial turnover by lysosomes. In this review we have documented the spectrum of biochemical defects identified in PD post-mortem brain and explored their relevance to metabolic pathways involved in neurodegeneration. We have highlighted the complex interactions between these pathways and the gene mutations causing or increasing risk for PD. These pathways are becoming a focus for the development of disease modifying therapies for PD.

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“…Recent studies have shown that MFGE8, which promotes phagocytosis and inhibits inflammation, is an endogenous protective factor in response to brain infarction ( 17 , 18 ), Alzheimer’s disease ( 19 , 20 ), subarachnoid hemorrhage (SAH) ( 16 ), and prion disease ( 21 ). However, Kinugawa et al reported that MFGE8 does not orchestrate the apoptotic neurons clearance in a Parkinson’s disease mouse model ( 22 ). Moreover, Neher et al found that MFGE8 −/− mice had therapeutic targets even with a lack of MFGE8 expression in transient cerebral ischemia ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

Milk Fat Globule-Epidermal Growth Factor-8 Pretreatment Attenuates Apoptosis and Inflammation via the Integrin-β3 Pathway after Surgical Brain Injury in Rats

Xiao

Chen

et al. 2018

Front. Neurol.

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Iatrogenic brain injury inevitably occurs in neurosurgical operations, leading to brain edema, ischemia, intracranial hematoma, and other postoperative complications, eventually worsening neurological outcomes of patients. If apoptotic cells are not rapidly eliminated by phagocytic engulfment, they may communicate with surrounding cells to undergo secondary necrosis and releasing toxic signals. Recent studies have shown that milk fat globule-epidermal growth factor-8 (MFGE8), which promotes phagocytosis and inhibits inflammation, is an endogenous protective factor in response to brain infarction, Alzheimer’s disease, subarachnoid hemorrhage, and prion disease. In the present study, we sought to investigate the different effects of both pretreated and posttreated recombinant milk fat globule-epidermal growth factor-8 (rhMFGE8) for the surgical brain injury (SBI) rat model and potential involvement of its receptor integrin β3 for apoptosis and neuroinflammation after SBI. One hundred and sixty-seven male rats were employed in the preset study. Experiment 1 was performed to evaluate neurological scores and MFGE8, cleaved caspase-3 (CC3), and interleukine-1 beta (IL-1β) levels at 3, 24, and 120 h after SBI. Experiment 2 was performed to evaluate the effects of rhMFGE8 pretreatment (10 min before SBI) and rhMFGE8 posttreatment (6 h after SBI) on brain edema at 24 and 72 h after SBI. Experiment 3 was performed to evaluate the potential anti-apoptotic and anti-inflammatory effects of rhMFGE8 pretreatment and posttreatment. Experiment 4 sought to investigate the involvement of the integrin-β3 signal in the effects of MFGE8 pretreatment. Our data showed rhMFGE8 pretreatment alleviated neurological deficits and decreased brain water content and apoptotic cells in the SBI model, which exhibited neurological dysfunction, apoptosis, and inflammation. Meanwhile, MFGE8 siRNA, which inhibited endogenous MFGE8 expression, significantly increased IL-1β, TUNEL positive cells, and CC3. Furthermore, knockdown of its receptor integrin β3 by siRNA abolished the effects of rhMFGE8 in the SBI model. In conclusion, we found that rhMFGE8 pretreatment effectively alleviated neurological deficits and decreased brain water content and apoptotic cells in the SBI model through the MFGE8/integrin-β3 pathway, and treatment time was an important factor in achieving curative effects. Therefore, MFGE8 pretreatment may serve as a promising therapeutic strategy for SBI patients.

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MFGE8 does not orchestrate clearance of apoptotic neurons in a mouse model of Parkinson's disease

Cited by 10 publications

References 34 publications

TGFβ1 increases microglia-mediated engulfment of apoptotic cells via upregulation of the milk fat globule-EGF factor 8

TGFβ1 increases microglia-mediated engulfment of apoptotic cells via upregulation of the milk fat globule-EGF factor 8

Molecular changes in the postmortem parkinsonian brain

Milk Fat Globule-Epidermal Growth Factor-8 Pretreatment Attenuates Apoptosis and Inflammation via the Integrin-β3 Pathway after Surgical Brain Injury in Rats

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