Microglia inhibit photoreceptor cell death and regulate immune cell infiltration in response to retinal detachment

Okunuki, Yoko; Mukai, Ryo; Pearsall, Elizabeth A.; Klokman, Garrett; Husain, Deeba; Park, Dong‐Ho; Korobkina, Ekaterina; Weiner, Howard L.; Butovsky, Oleg; Ksander, Bruce R.; Miller, Joan W.; Connor, Kip M.

doi:10.1073/pnas.1719601115

Cited by 122 publications

(122 citation statements)

References 71 publications

(110 reference statements)

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“…S4). These structures are similar to ones discovered as a result of photoreceptor degeneration after retinal detachment (Okunuki et al, 2018). There is increasing evidence that relates deficits in extracellular matrix with degenerative disorders like macular degeneration (Al-Ubaidi, Naash et al, 2013, Fernandez-Godino, Pierce et al, 2016.…”

Section: Discussionsupporting

confidence: 73%

“…In healthy retinas, microglial cells (Iba1+) displayed a ramified morphology, and are located specifically in the ganglion cell, and inner and outer plexiform layer (SI Appendix Fig. S3), as previously reported (Okunuki, Mukai et al, 2018). Interestingly, in IMPG2 KO mice we observed Iba1-positive cells invading the photoreceptor layers and the subretinal lesions ( Fig.…”

Section: Subretinal Lesions Are Rich In Impg1 Proteoglycan and Activasupporting

confidence: 83%

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Proteoglycan IMPG2 shapes the interphotoreceptor matrix and modulates vision

Salido

Ramamurthy

2019

Preprint

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AbstractThe extracellular matrix surrounding the photoreceptor neurons, interphotoreceptor matrix (IPM) is comprised of two unique proteoglycans: IPM proteoglycan 1 and 2 (IMPG1 and IMPG2). Although the functions of the IPM are not understood, patients with mutations in IMPG1/2 develop visual deficits with subretinal material accumulation. Here, we generated mouse models lacking IMPG1/2 to decipher the role of these proteoglycans and the pathological mechanisms that lead to vision loss. IMPG1 and IMPG2 occupy specific locations in the outer retina, and both proteoglycans are fundamental for the constitution of the IPM system. Mice lacking IMPG2 show abnormal accumulation of IMPG1, and in later stages, develop subretinal lesions and reduced visual function. Interestingly, removal of IMPG1-2 showed normal retinal morphology and function, suggesting that the aberrant localization of IMPG1 causes the alterations observed in IMPG2 KO mice. In conclusion, our results demonstrate the role of IMPG2 in shaping the IPM, shed light on the potential mechanisms leading to subretinal lesions, and show that the secreted proteoglycans depend on the extracellular matrix environment to properly integrate into the matrix.

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Section: Discussionsupporting

confidence: 73%

Section: Subretinal Lesions Are Rich In Impg1 Proteoglycan and Activasupporting

confidence: 83%

Proteoglycan IMPG2 shapes the interphotoreceptor matrix and modulates vision

Salido

Ramamurthy

2019

Preprint

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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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“…Microglia have been shown to accelerate degeneration by phagocytosing stressed but still living photoreceptors in a process termed phagoptosis (56); inhibition of this form of phagocytosis in the rd10 model by the blockade of the vitronectin receptor resulted in slowed degeneration (6), while its augmentation in CX3CR1 deficiency accelerated loss of photoreceptor structure and function (11). Conversely, in a model of retinal detachment, retinal microglia appear to support photoreceptor survival; when autofluorescent microglia, which presumably had phagocytosed photoreceptors, were pharmacologically depleted, degeneration was increased (57). We discover here in the rd10 retina that both C3 and CR3 participate in facilitating microglial phagocytosis of apoptotic photoreceptors; when either of these factors are deficient, decreased microglial phagocytosis was accompanied by increased accumulation of apoptotic cells, increased proinflammatory cytokine expression, and accelerated degeneration.…”

Section: Discussionmentioning

confidence: 99%

Complement C3- and CR3-dependent microglial clearance protects photoreceptors in retinitis pigmentosa

Silverman

Wang

et al. 2018

Preprint

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One Sentence Summary:Complement activation mediates adaptive neuroprotection for photoreceptors by facilitating C3-CR3 dependent microglial clearance of apoptotic cells. Abstract:Complement activation has been implicated as an inflammatory driver of neurodegeneration in retinal and brain pathologies. However, its involvement and influence of photoreceptor degeneration in retinitis pigmentosa (RP), an inherited, largely incurable blinding disease, is unclear. We discover that markedly upregulated retinal expression of multiple complement components coincided spatiotemporally with photoreceptor degeneration in both the rd10 mouse model and in human specimens of RP, with increased complement C3 expression and activation localizing to infiltrating microglia near photoreceptors. Genetic ablation of C3 in the rd10 background resulted in accelerated structural and functional photoreceptor degeneration and altered retinal expression of inflammatory genes. These effects were phenocopied by the genetic deletion of CR3, a microglia-expressed receptor for the C3 activation product C3b, implicating an adaptive microglial-mediation mechanism involving C3-CR3 interaction. Deficiency of either C3 or CR3 resulted in deficient microglial phagocytosis of apoptotic photoreceptors in vivo, as well as increased microglial neurotoxicity to photoreceptors in vitro. These findings demonstrate a novel adaptive role for complement activation in RP that facilitates microglial clearance of apoptotic photoreceptors, without which increased proinflammatory microglial neurotoxicity ensues. These positive contributions of complement via microglial-mediated mechanisms are important in the design of immunomodulatory therapeutic approaches to neurodegeneration.

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Microglia inhibit photoreceptor cell death and regulate immune cell infiltration in response to retinal detachment

Cited by 122 publications

References 71 publications

Proteoglycan IMPG2 shapes the interphotoreceptor matrix and modulates vision

Proteoglycan IMPG2 shapes the interphotoreceptor matrix and modulates vision

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

Complement C3- and CR3-dependent microglial clearance protects photoreceptors in retinitis pigmentosa

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