Dynamic changes in microglial and macrophage characteristics during degeneration and regeneration of the zebrafish retina

Mitchell, Diana; Lovel, Anna G; Stenkamp, Deborah L.

doi:10.1186/s12974-018-1185-6

Cited by 95 publications

(145 citation statements)

References 68 publications

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“…One feature of mTOR during retina regeneration was its early activation a few hours after injury and declination after 2 dpi (Figure ). Interestingly, previous studies showed that inflammation after retinal injury was also an early and transient event (Mitchell, Lovel, & Stenkamp, ; Zhang et al, ). We therefore asked whether retinal inflammation was connected to mTOR in the Müller glia.…”

Section: Resultsmentioning

confidence: 99%

Inflammation‐induced mammalian target of rapamycin signaling is essential for retina regeneration

Zhang

Hou

et al. 2019

Glia

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Upon retina injury, Müller glia in the zebrafish retina respond by generating multipotent progenitors to repair the retina. However, the complete mechanisms underlying retina regeneration remain elusive. Here we report inflammation‐induced mammalian target of rapamycin (mTOR) signaling in the Müller glia is essential for retina regeneration in adult zebrafish. We show after a stab injury, mTOR is rapidly activated in Müller glia and later Müller glia‐derived progenitor cells (MGPCs). Importantly, mTOR is required for Müller glia dedifferentiation, as well as the proliferation of Müller glia and MGPCs. Interestingly, transient mTOR inhibition by rapamycin only reversibly suppresses MGPC proliferation, while its longer suppression by knocking down Raptor significantly inhibits the regeneration of retinal neurons. We further show mTOR promotes retina regeneration by regulating the mRNA expression of key reprogramming factors ascl1a and lin‐28a, cell cycle‐related genes and critical cytokines. Surprisingly, we identify microglia/macrophage‐mediated inflammation as an important upstream regulator of mTOR in the Müller glia and it promotes retina regeneration through mTOR. Our study not only demonstrates the important functions of mTOR but also reveals an interesting link between inflammation and the mTOR signaling during retina regeneration.

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Section: Resultsmentioning

confidence: 99%

Inflammation‐induced mammalian target of rapamycin signaling is essential for retina regeneration

Zhang

Hou

et al. 2019

Glia

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“…Degenerated photoreceptors are eliminated in the absence of microglia/macrophage infiltration. Previous studies have reported that degenerated photoreceptors are eliminated by professional phagocytes such as microglia and macrophages [15][16][17][18][19][20] . Therefore, we conducted immunofluorescence for Iba1, a microglia/macrophage marker, in combination with TdT-mediated dUTP nick end labeling (TUNEL) assay to assess whether degenerated photoreceptors were eliminated by microglia/macrophages (hereafter referred to collectively as macrophages) also in our retinal injury model.…”

Section: Resultsmentioning

confidence: 99%

“…There is controversy as to which cell type or types are predominantly involved in the phagocytic removal of degenerated cells in the retina. While many studies have suggested the primary role of professional phagocytes such as microglia or bone marrow-derived macrophages [15][16][17][18][19][20] , other cell types such as Müller glia are also reported to show phagocytic activity during development 34,35 or under pathological conditions [22][23][24][25] . A recent report has further suggested that Müller glia play a predominant phagocytic role during the early stage of photoreceptor degeneration in RhoP23H/P23H mice 36 .…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylserine recognition and Rac1 activation are required for Müller glia proliferation, gliosis and phagocytosis after retinal injury

Nomura-Komoike

Saitoh

Fujieda

2020

Sci Rep

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Müller glia, the principal glial cell type in the retina, have the potential to reenter the cell cycle after retinal injury. In mammals, proliferation of Müller glia is followed by gliosis, but not regeneration of neurons. Retinal injury is also accompanied by phagocytic removal of degenerated cells. We here investigated the possibility that proliferation and gliosis of Müller glia and phagocytosis of degenerated cells may be regulated by the same molecular pathways. After N-methyl-N-nitrosourea-induced retinal injury, degenerated photoreceptors were eliminated prior to the infiltration of microglia/macrophages into the outer nuclear layer, almost in parallel with cell cycle reentry of Müller glia. Inhibition of microglia/macrophage activation with minocycline did not affect the photoreceptor clearance. Accumulation of lysosomes and rhodopsin-positive photoreceptor debris within the cytoplasm of Müller glia indicated that Müller glia phagocytosed most photoreceptor debris. Pharmacological inhibition of phosphatidylserine and Rac1, key regulators of the phagocytic pathway, prevented cell cycle reentry, migration, upregulation of glial fibrillary acidic protein, and phagocytic activity of Müller glia. These data provide evidence that phosphatidylserine and Rac1 may contribute to the crosstalk between different signaling pathways activated in Müller glia after injury.Müller glia, the principal glial cells in the retina, possess a variety of functions to support retinal neurons and act to maintain retinal homeostasis under physiological as well as pathological conditions 1,2 . In lower vertebrates like fish, retinal injury induces Müller glia to proliferate and dedifferentiate to neuronal progenitor cells that are capable of regenerating retinal neurons 3,4 . In mammals, however, such regenerative capacity of Müller glia is extremely limited. In rats, for example, Müller glia proliferate in response to injury, but they quickly exit the cell cycle and many undergo cell death possibly by DNA damage response 5 . In addition, Müller glia in mammals show a set of injury-induced responses called reactive gliosis, including cellular hypertrophy, migration, and upregulation of intermediate filaments such as glial fibrillary acidic protein (GFAP) and vimentin 6 . Although gliosis may be neuroprotective, it may hamper tissue repair if the reaction is prolonged 6 .Previous evidence has indicated that the injury-induced responses of Müller glia are mediated by growth factors or cytokines secreted from damaged neurons, microglia, or Müller glia themselves 6-8 . A pioneering study by Rattner and Nathans 9 showed that damaged photoreceptors produce endothelin2 (Edn2), which signals onto Müller glia and induces their reactive responses such as GFAP upregulation. However, the Edn2-mediated interaction between damaged photoreceptors and Müller glia seems to be initiated by Leukemia inhibitory factor (LIF) release from Müller glia 10 . Upregulation of LIF has been observed in a variety of retinal injury models 10-13 , and TNFα may be i...

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“…For example, dysregulated microglial phagocytosis may contribute to pathology in a variety of neurodegenerative diseases . In contrast, microglial phagocytosis limits secondary cell death in contexts of acute CNS injury and is important in response to widespread retinal lesion in zebrafish . Therefore, a better understanding of molecular mechanisms and pathways functioning in microglial phagocytosis in healthy vs damaged or diseased tissue are likely to yield important targets to modulate and balance microglial behavior in vivo.…”

Section: Discussionmentioning

confidence: 99%

Microglia in the developing retina couple phagocytosis with the progression of apoptosis via P2RY12 signaling

Blume

Lambert

Lovel

et al. 2020

Developmental Dynamics

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Background: Microglia colonize the developing vertebrate central nervous system coincident with the detection of developmental apoptosis. Our understanding of apoptosis in intact tissue in relation to microglial clearance of dying cells is largely based on fixed samples, which is limiting given that microglia are highly motile and mobile phagocytes. Here, we used a system of microglial depletion and in vivo real-time imaging in zebrafish to directly address microglial phagocytosis of apoptotic cells during normal retinal development, the relative timing of phagocytosis in relation to apoptotic progression, and the contribution of P2RY12 signaling to this process. Results: The depletion of microglia resulted in accumulation of numerous apoptotic cells in the retina. Real-time imaging revealed precise timing of microglial engulfment with the progression of apoptosis, and dynamic movement and displacement of engulfed apoptotic cells. Inhibition of P2RY12 signaling delayed microglial clearance of apoptotic cells. Conclusions: Microglial engulfment of dying cells is coincident with apoptotic progression and requires P2RY12 signaling, indicating that microglial P2RY12 signaling is shared between development and injury response. Our work provides important in vivo insight into the dynamics of apoptotic cell clearance in the developing vertebrate retina and provides a basis to understand microglial phagocytic behavior in health and disease. K E Y W O R D S developmental apoptosis, microglia, p2ry12, phagocytosis, retina, zebrafish

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Dynamic changes in microglial and macrophage characteristics during degeneration and regeneration of the zebrafish retina

Cited by 95 publications

References 68 publications

Inflammation‐induced mammalian target of rapamycin signaling is essential for retina regeneration

Inflammation‐induced mammalian target of rapamycin signaling is essential for retina regeneration

Phosphatidylserine recognition and Rac1 activation are required for Müller glia proliferation, gliosis and phagocytosis after retinal injury

Microglia in the developing retina couple phagocytosis with the progression of apoptosis via P2RY12 signaling

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