Early Microglia Activation Precedes Photoreceptor Degeneration in a Mouse Model of CNGB1-Linked Retinitis Pigmentosa

Blank, Thomas; Goldmann, Tobias; Koch, Mirja; Amann, Lukas; Schön, Christian; Bonin, Michael; Pang, Shengru; Prinz, Marco; Burnet, Michael; Wagner, Johanna; Biel, Martin; Michalakis, Stylianos

doi:10.3389/fimmu.2017.01930

Cited by 37 publications

(30 citation statements)

References 58 publications

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“…Inflammation has been reported mostly at advanced stages of RP in retina that has already partly degenerated and in which retinal cells continue to die ( 31 , 33 , 54 – 56 ). However, precedent exists that microglia activation may occur early, preceding any retinal cell death, and contribute to degenerative processes ( 57 ). Microglia may have protective roles ( 24 , 58 ) or promote photoreceptor cell death increasing the severity of retinal degeneration ( 29 , 40 , 59 ).…”

Section: Discussionmentioning

confidence: 99%

Microglia Inhibition Delays Retinal Degeneration Due to MerTK Phagocytosis Receptor Deficiency

2020

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Retinitis Pigmentosa (RP) is a group of inherited retinal diseases characterized by progressive loss of rod followed by cone photoreceptors. An especially early onset form of RP with blindness in teenage years is caused by mutations in mertk, the gene encoding the clearance phagocytosis receptor Mer tyrosine kinase (MerTK). The cause for blindness in mutant MerTK-associated RP (mutMerTK-RP) is the failure of retinal pigment epithelial cells in diurnal phagocytosis of spent photoreceptor outer segment debris. However, the early onset and very fast progression of degeneration in mutMerTK-RP remains unexplained. Here, we explored the role of microglia in the Royal College of Surgeons (RCS) rat model of mutMerTK-RP. We found elevated levels of inflammatory cytokines and CD68 microglia activation marker, and more ionized calcium-binding adapter molecule 1 (Iba-1) positive microglia in RCS retina when compared to wild-type retina as early as postnatal day 14 (P14). Strikingly, renewal of photoreceptor outer segments in P14 wild-type rat retina is still immature with low levels of RPE phagocytosis implying that at this early age lack of this process in RCS rats is unlikely to distress photoreceptors. Although the total number of Iba-1 positive retinal microglia remains constant from P14 to P30, we observed increasing numbers of microglia in the outer retina from P20 implying migration to the outer retina before onset of photoreceptor cell death at ∼P25. Iba-1 and CD68 levels also increase in the retina during this time period suggesting microglia activation. To determine whether microglia affect the degenerative process, we suppressed retinal microglia in vivo using tamoxifen or a combination of tamoxifen and liposomal clodronate. Treatments partly prevented elevation of Iba-1 and CD68 and relocalization of microglia. Moreover, treatments led to partial but significant retention of photoreceptor viability and photoreceptor function. We conclude that loss of the phagocytosis receptor MerTK causes microglia activation and relocalization in the retina before lack of RPE phagocytosis causes overt retinal degeneration, and that microglia activities accelerate loss of photoreceptors in mutMerTK-RP. These results suggest that therapies targeting microglia may delay onset and slow the progression of this blinding disease.

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Section: Discussionmentioning

confidence: 99%

Microglia Inhibition Delays Retinal Degeneration Due to MerTK Phagocytosis Receptor Deficiency

2020

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“…In many animal models of RP, increased infiltration of activated microglia, Müller glia and macrophages occurs before or during the early stages of rod degeneration [ 99 , 100 , 101 , 102 ]. Circulating monocyte-derived macrophages have been suggested to promote rod cell death in RP since ablation of Ccr2, the receptor for the monocyte chemoattractant MCP-1, reduced retinal degeneration in rd10 mice [ 103 ].…”

Section: Recruitment and Activation Of Microglia And Monocytesmentioning

confidence: 99%

Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

Newton

Megaw

2020

Genes

145

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Retinitis pigmentosa (RP) is the most common cause of inherited blindness and is characterised by the progressive loss of retinal photoreceptors. However, RP is a highly heterogeneous disease and, while much progress has been made in developing gene replacement and gene editing treatments for RP, it is also necessary to develop treatments that are applicable to all causative mutations. Further understanding of the mechanisms leading to photoreceptor death is essential for the development of these treatments. Recent work has therefore focused on the role of apoptotic and non-apoptotic cell death pathways in RP and the various mechanisms that trigger these pathways in degenerating photoreceptors. In particular, several recent studies have begun to elucidate the role of microglia and innate immune response in the progression of RP. Here, we discuss some of the recent progress in understanding mechanisms of rod and cone photoreceptor death in RP and summarise recent clinical trials targeting these pathways.

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“…Genetic deletion of Cngb1 in mice results in a phenotype that recapitulates the principal pathology of RP patients. In particular, Cngb1 knockout (KO) mice have strongly diminished rod photoreceptor function and impaired rod-mediated vision [ 55 , 56 , 57 ]. The early functional defects are followed by a progressive degeneration of rods and secondary degeneration of primarily non-affected cones.…”

Section: In Vivo Analysis Of Cng Channel Function: Analysis Of Genmentioning

confidence: 99%

“…The early functional defects are followed by a progressive degeneration of rods and secondary degeneration of primarily non-affected cones. The degeneration process is rather slow and results in loss of about 50% of rods at 6 months and 90% at 12 months of age [ 55 , 57 , 58 ]. At the cellular level, the loss of Cngb1 induces down-regulation of several proteins of the phototransduction cascade and degradation of the CNGA1 subunit.…”

Section: In Vivo Analysis Of Cng Channel Function: Analysis Of Genmentioning

confidence: 99%

Retinal Cyclic Nucleotide-Gated Channels: From Pathophysiology to Therapy

Michalakis

Becirovic

Biel

2018

IJMS

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The first step in vision is the absorption of photons by the photopigments in cone and rod photoreceptors. After initial amplification within the phototransduction cascade the signal is translated into an electrical signal by the action of cyclic nucleotide-gated (CNG) channels. CNG channels are ligand-gated ion channels that are activated by the binding of cyclic guanosine monophosphate (cGMP) or cyclic adenosine monophosphate (cAMP). Retinal CNG channels transduce changes in intracellular concentrations of cGMP into changes of the membrane potential and the Ca2+ concentration. Structurally, the CNG channels belong to the superfamily of pore-loop cation channels and share a common gross structure with hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and voltage-gated potassium channels (KCN). In this review, we provide an overview on the molecular properties of CNG channels and describe their physiological role in the phototransduction pathways. We also discuss insights into the pathophysiological role of CNG channel proteins that have emerged from the analysis of CNG channel-deficient animal models and human CNG channelopathies. Finally, we summarize recent gene therapy activities and provide an outlook for future clinical application.

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Early Microglia Activation Precedes Photoreceptor Degeneration in a Mouse Model of CNGB1-Linked Retinitis Pigmentosa

Cited by 37 publications

References 58 publications

Microglia Inhibition Delays Retinal Degeneration Due to MerTK Phagocytosis Receptor Deficiency

Microglia Inhibition Delays Retinal Degeneration Due to MerTK Phagocytosis Receptor Deficiency

Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

Retinal Cyclic Nucleotide-Gated Channels: From Pathophysiology to Therapy

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