Cell-Type-Specific Complement Expression in the Healthy and Diseased Retina

Pauly, Diana; Agarwal, Divyansh; Dana, Nicholas; Schäfer, Nicole; Biber, Josef; Wunderlich, Kirsten A.; Jabri, Yassin; Straub, Tobias; Zhang, Nancy R.; Gautam, Avneesh; Weber, Bernhard H. F.; Hauck, Stefanie M.; Kim, Mijin; Curcio, Christine A.; Stambolian, Dwight; Li, Mingyao; Grosche, Antje

doi:10.1016/j.celrep.2019.10.084

Cited by 80 publications

(133 citation statements)

References 63 publications

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“…weekold ABCA4 −/− mice and compared to previously published wild-type data [19]. We found a week-old ABCA4 −/− mice and compared to previously published wild-type data [19]. We found a significantly enhanced expression of c3 in RPE cells and decreased expression of cfi in microglia cells compared to wild-type controls.…”

Section: Increase Of C3 Cleavage Products In Abca4 −/− Mice Compared supporting

confidence: 66%

“…Cfi, a cofactor of CFH, was downregulated at the RNA level with aging in microglia, while it was expressed at increasing levels in the RPE. weekold ABCA4 −/− mice and compared to previously published wild-type data [19]. We found a week-old ABCA4 −/− mice and compared to previously published wild-type data [19].…”

Section: Increase Of C3 Cleavage Products In Abca4 −/− Mice Compared supporting

confidence: 54%

“…Photoreceptor density, as determined by quantification of DAPI+ cell nuclei in the outer nuclear layer (ONL), was significantly decreased in ABCA4 −/− and wild-type mice at 32 weeks of age and older [19]. (C) The integrity and autofluorescence of the retinal pigment epithelium (RPE) were investigated in fixed, flat-mounted eyecup preparations after careful removal (GCL) is observed in ABCA4 −/− mice aged 24, 32 and 40 weeks but not in the albino wild-type retina (data were obtained previously) [19]. Cell numbers in the retinal inner nuclear layer (INL) were stable in aging ABCA4 −/− mice.…”

Section: Introductionmentioning

confidence: 99%

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Cell-Type-Specific Complement Profiling in the ABCA4−/− Mouse Model of Stargardt Disease

Jabri

Biber

Díaz‐Lezama

et al. 2020

IJMS

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Stargardt macular degeneration is an inherited retinal disease caused by mutations in the ATP-binding cassette subfamily A member 4 (ABCA4) gene. Here, we characterized the complement expression profile in ABCA4−/− retinae and aligned these findings with morphological markers of retinal degeneration. We found an enhanced retinal pigment epithelium (RPE) autofluorescence, cell loss in the inner retina of ABCA4−/− mice and demonstrated age-related differences in complement expression in various retinal cell types irrespective of the genotype. However, 24-week-old ABCA4−/− mice expressed more c3 in the RPE and fewer cfi transcripts in the microglia compared to controls. At the protein level, the decrease of complement inhibitors (complement factor I, CFI) in retinae, as well as an increased C3b/C3 ratio in the RPE/choroid and retinae of ABCA4−/−, mice was confirmed. We showed a corresponding increase of the C3d/C3 ratio in the serum of ABCA4−/− mice, while no changes were observed for CFI. Our findings suggest an overactive complement cascade in the ABCA4−/− retinae that possibly contributes to pathological alterations, including microglial activation and neurodegeneration. Overall, this underpins the importance of well-balanced complement homeostasis to maintain retinal integrity.

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Section: Increase Of C3 Cleavage Products In Abca4 −/− Mice Compared supporting

confidence: 66%

Section: Increase Of C3 Cleavage Products In Abca4 −/− Mice Compared supporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cell-Type-Specific Complement Profiling in the ABCA4−/− Mouse Model of Stargardt Disease

Jabri

Biber

Díaz‐Lezama

et al. 2020

IJMS

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“…Microglia also produce complement proteins and regulators which contribute to retinal homeostasis and disease ( 89 , 90 ). While microglia are known to express C1q, cytokines (IL-1 β , IL-6, and TNF- α ) can induce the secretion of C1r, C1s, and C3 by astrocytes and microglia ( 91 ).…”

Section: Mediators Of Inflammation In Diabetic Retinopathymentioning

confidence: 99%

Microglia and Inflammatory Responses in Diabetic Retinopathy

2020

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Diabetic retinopathy is a vision-threatening disease affecting neurons and microvasculature of the retina. The development of this disease is associated with the action of inflammatory factors that are connected to the activation of microglial cells, the resident tissue macrophages of the CNS. In the quiescent state, microglial cells help maintain tissue homeostasis in the retina through phagocytosis and control of low-grade inflammation. However, prolonged tissue stress due to hyperglycemia primes microglia to become overly reactive with the concomitant production of pro-inflammatory cytokines and chemokines causing chronic inflammation. In this review, we provide evidence of microglial cell activation and pro-inflammatory molecules associated with the development and progression of diabetic retinopathy. We further highlight innovative animal models that can mimic the disease in humans and discuss strategies in modulating microglial-mediated inflammation as potential therapeutic approaches in managing the disease.

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“…This result indicates that CNTF broadly impacts different retinal cell types under degeneration conditions, either directly or indirectly. It is also known that different retinal cell types express complement pathway components 43 . Our results captured changes of various complement genes, suggesting that CNTF may regulate this important system and influence their functions in the adult retina.…”

Section: Discussionmentioning

confidence: 99%

Impacts of ciliary neurotrophic factor on the retinal transcriptome in a mouse model of photoreceptor degeneration

Wang

Rhee

Pellegrini

et al. 2020

Sci Rep

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ciliary neurotrophic factor (cntf) has been tested in clinical trials for human retinal degeneration due to its potent neuroprotective effects in various animal models. To decipher CNTF-triggered molecular events in the degenerating retina, we performed high-throughput RnA sequencing analyses using the Rds/Prph2 (P216L) transgenic mouse as a preclinical model for retinitis pigmentosa. In the absence of cntf treatment, transcriptome alterations were detected at the onset of rod degeneration compared with wild type mice, including reduction of key photoreceptor transcription factors Crx, Nrl, and rod phototransduction genes. Short-term CNTF treatments caused further declines of photoreceptor transcription factors accompanied by marked decreases of both rod-and cone-specific gene expression. in addition, cntf triggered acute elevation of transcripts in the innate immune system and growth factor signaling. These immune responses were sustained after long-term CNTF exposures that also affected neuronal transmission and metabolism. Comparisons of transcriptomes also uncovered common pathways shared with other retinal degeneration models. Cross referencing bulk RNA-seq with single-cell RnA-seq data revealed the cntf responsive cell types, including Müller glia, rod and cone photoreceptors, and bipolar cells. Together, these results demonstrate the influence of exogenous cntf on the retinal transcriptome landscape and illuminate likely cntf impacts in degenerating human retinas. Retinal degeneration (RD) is known as an irreversible, progressive neurologic disorder caused by genetic mutations and/or environmental or pathological damage to the retina. One therapeutic strategy to attenuate vision loss in disease conditions is treating the retina with neuroprotective agents that promote neuronal viability. Ciliary neurotrophic factor (CNTF) has been shown to be a potent neuroprotective agent for various types of retinal degenerations, including those caused by gene mutations, light-induced damage, and physical injury 1. Since CNTF enhances the survival of both photoreceptors and retinal ganglion cells, the two major cell classes damaged in retinal degenerative diseases, a CNTF-based therapy has been developed and tested in several clinical trials. To date, outcomes of the trials for retinitis pigmentosa, geographic atrophy, and achromatopsia have not demonstrated sufficient therapeutic benefits for human patients 2-5. However, CNTF therapy for macular telangiectasia type 2 has shown efficacy 6,7 , and a clinical trial for the second largest blinding disease glaucoma 8 is ongoing (https://clinicaltrials.gov/ct2/show/NCT01408472). To shed light on the molecular and cellular mechanisms of CNTF-mediated neuroprotection, we have delivered the same secreted recombinant CNTF used in human trials to a mouse model expressing the Rds/peripherin2 (Prph2) transgene with the P216L mutation 9. Pheripherin2 is a structural protein of the photoreceptor outer segment disc, and over 80 PRPH2 pathological mutations have been linked to RD, with...

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Cell-Type-Specific Complement Expression in the Healthy and Diseased Retina

Cited by 80 publications

References 63 publications

Cell-Type-Specific Complement Profiling in the ABCA4−/− Mouse Model of Stargardt Disease

Cell-Type-Specific Complement Profiling in the ABCA4−/− Mouse Model of Stargardt Disease

Microglia and Inflammatory Responses in Diabetic Retinopathy

Impacts of ciliary neurotrophic factor on the retinal transcriptome in a mouse model of photoreceptor degeneration

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