MMP Inhibition Preserves Integrin Ligation and FAK Activation to Induce Survival and Regeneration in RGCs Following Optic Nerve Damage

D'Onofrio, Philippe M; Shabanzadeh, Alireza P.; Choi, Brian; Bähr, Mathias; Koeberle, Paulo D.

doi:10.1167/iovs.18-25257

Cited by 16 publications

(16 citation statements)

References 60 publications

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“…Its importance in physiology and disease was quickly recognised and a host of cellular and in vivo studies have since placed FAK as a key player of cellular processes which in some form usually require controlled cell motility. As such, FAK is required for various aspects during development [3][4][5][6] as well as tissue regeneration and wound healing [7][8][9][10]. The importance of FAK in cell motility is also reflected in disease where FAK plays major roles in tumour invasion and metastasis [11].…”

Section: Introductionmentioning

confidence: 99%

FAK Structure and Regulation by Membrane Interactions and Force in Focal Adhesions

2020

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Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase with key roles in the regulation of cell adhesion migration, proliferation and survival. In cancer FAK is a major driver of invasion and metastasis and its upregulation is associated with poor patient prognosis. FAK is autoinhibited in the cytosol, but activated upon localisation into a protein complex, known as focal adhesion complex. This complex forms upon cell adhesion to the extracellular matrix (ECM) at the cytoplasmic side of the plasma membrane at sites of ECM attachment. FAK is anchored to the complex via multiple sites, including direct interactions with specific membrane lipids and connector proteins that attach focal adhesions to the actin cytoskeleton. In migrating cells, the contraction of actomyosin stress fibres attached to the focal adhesion complex apply a force to the complex, which is likely transmitted to the FAK protein, causing stretching of the FAK molecule. In this review we discuss the current knowledge of the FAK structure and how specific structural features are involved in the regulation of FAK signalling. We focus on two major regulatory mechanisms known to contribute to FAK activation, namely interactions with membrane lipids and stretching forces applied to FAK, and discuss how they might induce structural changes that facilitate FAK activation.

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Section: Introductionmentioning

confidence: 99%

FAK Structure and Regulation by Membrane Interactions and Force in Focal Adhesions

2020

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“…To further elucidate the underlying mechanisms of this tightening process, we choose to investigate a role for MMP‐3, a protease that has been shown to importantly contribute to barrier dysfunction in the injured and diseased CNS (Brkic, Balusu, Libert, & Vandenbroucke, 2015; Brkic, Balusu, Van Wonterghem, et al, 2015; Chung et al, 2013; Grossetete, Phelps, Arko, Yonas, & Rosenberg, 2009; Jalal, Yang, Thompson, Lopez, & Rosenberg, 2012; Van Hove et al, 2016), and that was reported to be highly upregulated immediately after ONC (Agudo et al, 2008; D'Onofrio et al, 2019; Thompson et al, 2018; Yang et al, 2007). This temporary increase in MMP‐3 upon ONC was confirmed by our spatiotemporal expression study of MMP‐3.…”

Section: Discussionmentioning

confidence: 99%

“…Next, to study the explicit role and the underlying mechanisms of glia limitans tightening in vivo, an optic nerve crush (ONC) was applied, which induces retinal neurodegeneration and ‐inflammation (Bollaerts, Van Houcke, Andries, De Groef, & Moons, 2017; De Groef et al, 2016; Mac Nair, Schlamp, Montgomery, Shestopalov, & Nickells, 2016), and in which a tightening of the glia limitans at the NVU of the retina was confirmed. Second, given its prominent upregulation following optic nerve injury (Agudo et al, 2008; D'Onofrio, Shabanzadeh, Choi, Bahr, & Koeberle, 2019; Thompson et al, 2018; Yang et al, 2007) and previous reports ascribing a role in blood‐CNS barrier dysfunction and neuroinflammation (Brkic, Balusu, Libert, & Vandenbroucke, 2015; Hafez, Abdelsaid, Fagan, & Ergul, 2018; Kim & Hwang, 2011; Rosenberg, 2009; Van Hove et al, 2016; Van Hove, Lemmens, Van de Velde, Verslegers, & Moons, 2012), we focused on the role of matrix metalloproteinase‐3 (MMP‐3 or stromelysin‐1) at the glia limitans. Here, we show that mice lacking a functional Mmp3 gene have less or no induction of glia limitans TJMs and that this is accompanied by an increased infiltration of inflammatory cells and an augmented retinal ganglion cell (RGC) death shortly after ONC.…”

Section: Introductionmentioning

confidence: 99%

Tightening the retinal glia limitans attenuates neuroinflammation after optic nerve injury

Lefevere

Salinas‐Navarro

Andries

et al. 2020

Glia

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Increasing evidence suggests that functional impairments at the level of the neurovascular unit (NVU) underlie many neurodegenerative and neuroinflammatory diseases. While being part of the NVU, astrocytes have been largely overlooked in this context and only recently, tightening of the glia limitans has been put forward as an important neuroprotective response to limit these injurious processes. In this study, using the retina as a central nervous system (CNS) model organ, we investigated the structure and function of the glia limitans, and reveal that the blood-retina barrier and glia limitans function as a coordinated double barrier to limit infiltration of leukocytes and immune molecules. We provide in vitro and in vivo evidence for a protective response at the NVU upon CNS injury, which evokes inflammation-induced glia limitans tightening. Matrix metalloproteinase-3 (MMP-3) was found to be a crucial regulator of this process, thereby revealing its beneficial and immunomodulatory role in the CNS. in vivo experiments in which MMP-3 activity was deleted via genetic and pharmacological approaches, combined with a comprehensive study of tight junction molecules, glial end feet markers, myeloid cell infiltration, cytokine expression and neurodegeneration, show that MMP-3 attenuates neuroinflammation and neurodegeneration by tightening the glia limitans, thereby pointing to a prominent role of MMP-3 in preserving the integrity of the NVU upon injury. Finally, we gathered promising evidence to suggest that IL1b, which is also regulated by MMP-3, is at least one of the molecular messengers that induces glia limitans tightening in the injured CNS.

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“…The inhibition of matrix metalloproteinases (MMPs) significantly increased RGC axon regeneration. Focal adhesion kinase (FAK) inhibition reduced RGC survival and abrogated the neuroprotective effects of MMP inhibition, whereas FAK activation increased RGC survival despite MMP activation [ 52 ]. Therefore, the effects of FAK were dominant over those of MMPs.…”

Section: Factors That Affect Rgc Axon Regenerationmentioning

confidence: 99%

Advances in Regeneration of Retinal Ganglion Cells and Optic Nerves

Yuan

Wang

Jin

et al. 2021

IJMS

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Glaucoma, the second leading cause of blindness worldwide, is an incurable neurodegenerative disorder due to the dysfunction of retinal ganglion cells (RGCs). RGCs function as the only output neurons conveying the detected light information from the retina to the brain, which is a bottleneck of vision formation. RGCs in mammals cannot regenerate if injured, and RGC subtypes differ dramatically in their ability to survive and regenerate after injury. Recently, novel RGC subtypes and markers have been uncovered in succession. Meanwhile, apart from great advances in RGC axon regeneration, some degree of experimental RGC regeneration has been achieved by the in vitro differentiation of embryonic stem cells and induced pluripotent stem cells or in vivo somatic cell reprogramming, which provides insights into the future therapy of myriad neurodegenerative disorders. Further approaches to the combination of different factors will be necessary to develop efficacious future therapeutic strategies to promote ultimate axon and RGC regeneration and functional vision recovery following injury.

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MMP Inhibition Preserves Integrin Ligation and FAK Activation to Induce Survival and Regeneration in RGCs Following Optic Nerve Damage

Cited by 16 publications

References 60 publications

FAK Structure and Regulation by Membrane Interactions and Force in Focal Adhesions

FAK Structure and Regulation by Membrane Interactions and Force in Focal Adhesions

Tightening the retinal glia limitans attenuates neuroinflammation after optic nerve injury

Advances in Regeneration of Retinal Ganglion Cells and Optic Nerves

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