Vitreous Cytokine Expression and a Murine Model Suggest a Key Role of Microglia in the Inflammatory Response to Retinal Detachment

Kiang, Lee; Ross, Bing X; Yao, Jingyu; Shanmugam, Sumathi; Andrews, Chris; Hansen, Sean; Besirli, Cagri G.; Zacks, David N.; Abcouwer, Steve F.

doi:10.1167/iovs.18-24489

Cited by 39 publications

(66 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our analysis of vitreous samples con rms that RD in humans is associated with increased expression of cytokines, chemokines and growth factors [6,7,9,44]. Interestingly, our experimental model revealed a very similar induction in RD in mice, making it therefore well-suited for studying the effect of these mediators on RD-associated cone loss.…”

Section: Discussionsupporting

confidence: 53%

“…Although evidence from both human and experimental studies show that in ammation is strongly associated with RD-induced photoreceptor cell death [7,[10][11][12][13], little is known about the mechanisms that speci cally lead to cone death.…”

Section: Discussionmentioning

confidence: 99%

“…Several pathogenic mechanisms have been identi ed but accumulating evidence suggests that in ammation plays a key role in the pathogenesis of RD-induced rod-photoreceptor cell death. Human studies have thus reported elevated levels of cytokines and chemokines in the vitreous of patients with RD [6][7][8][9]. Furthermore, experimental models have demonstrated that cytokines from in ltrating mononuclear phagocytes (MP) induce the death of rods following retinal detachment [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Stimulation of Insulin Signaling Reverses Inflammation-Induced Cone Death in Retinal Detachment

Conart

Blot

Augustin

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Rhegmatogenous retinal detachment (RD) involving the macula is a major cause of visual impairment despite high surgical success rate, mainly because of cone death. We and others have shown that cone loss occurs secondary to chronic inflammation in many retinal diseases, including age-related macular degeneration and retinitis pigmentosa. We here investigated the yet unknown mechanisms of inflammation-induced cone death in RD.Methods Vitreous samples from patients with RD and from control patients with macular hole were analyzed to characterize the inflammatory response to RD. A mouse model of RD and retinal explants culture were then used to explore the mechanisms leading to cone death.Results Analysis of vitreous samples shows that RD induces a marked inflammatory response with increased cytokine and chemokine expression in humans, which is closely mimicked by experimental murine RD. In this model, we demonstrate that myeloid cells and T-lymphocytes directly contribute to cone loss, as the inhibition of their accumulation by Thrombospondin 1 increased cone survival. We show that cones are highly dependent on glucose and insulin signaling for survival in vitro and that insulin, and the insulin sensitizers rosiglitazone and metformin, prevent RD-induced cone loss in vivo, despite the persistence of inflammation.Conclusion Our results describe a new mechanism by which inflammation, likely through a combination of competition for glucose and the inhibition of insulin signaling, promotes cone death in RD. Therapeutic inhibition of inflammation and stimulation of insulin signaling might prevent RD-associated cone death until the RD can be surgically repaired and improve visual outcome after RD.Trial registration: ClinicalTrials.gov Identifier NCT03318588

show abstract

Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Stimulation of Insulin Signaling Reverses Inflammation-Induced Cone Death in Retinal Detachment

Conart

Blot

Augustin

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…[26][27][28] Microglia, which regulate macrophage infiltration, proliferate and infiltrate through the retina and into the subretinal space within days of detachment. 29,30 peritoneal macrophages injected into the vitreous of the rabbit trans-differentiate into fibroblast-like cells and initiate intraretinal fibrosis similar to that seen in PVR. 31 Macrophages clear retinal debris, alter vitreal structure through matrix protein-proteolysis and secrete fibroblast growth factor (FGF) and transforming growth factor-beta (TGFβ) which stimulate the accumulation and proliferation of fibroblast-like-cells within the incipient PVR epiretinal membranes.…”

Section: Inflammatory Phasementioning

confidence: 87%

Inflammatory and Fibrogenic Factors in Proliferative Vitreoretinopathy Development

Chaudhary

Scott²,

Wallace

et al. 2020

Trans. Vis. Sci. Tech.

View full text Add to dashboard Cite

Citation: Chaudhary R, Scott RAH, Wallace G, Berry M, Logan A, Blanch RJ. Inflammatory and fibrogenic factors in proliferative vitreoretinopathy development. Trans Vis Sci Tech. 2020;9(3):23, https://doi.org/10.1167/tvst.9.3.23Purpose: Proliferative vitreoretinopathy (PVR) occurs in 5%-10% of rhegmatogenous retinal detachment cases and is the principle cause for failure of retinal reattachment surgery. Although there are a number of surgical adjunctive agents available for preventing the development of PVR, all have limited efficacy. Discovering predictive molecular biomarkers to determine the probability of PVR development after retinal reattachment surgery will allow better patient stratification for more targeted drug evaluations.Methods: Narrative literature review. Results:We provide a summary of the inflammatory and fibrogenic factors found in ocular fluid samples during the development of retinal detachment and PVR and discuss their possible use as molecular PVR predictive biomarkers. Conclusions:Studies monitoring the levels of the above factors have found that few if any have predictive biomarker value, suggesting that widening the phenotype of potential factors and a combinatorial approach are required to determine predictive biomarkers for PVR.Translational Relevance: The identification of relevant biomarkers relies on an understanding of disease signaling pathways derived from basic science research. We discuss the extent to which those molecules identified as biomarkers and predictors of PVR relate to disease pathogenesis and could function as useful disease predictors.

show abstract

“…The duration of macular detachment influences visual outcome greatly, because proapoptotic factors and inflammation cytokines become significantly upregulated with increasing duration of separation. Such upregulation leads to more disruption of the EZ and worse BCVA after surgery 26,27 . In this study, we only included pseudophakic macula-off RRD patients with detachment duration less than 72 hours to avoid time bias and influences of lens opacity.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection with rasagiline in patients with macula-off retinal detachment: A randomized controlled pilot study

Framme

Menke

et al. 2020

Sci Rep

View full text Add to dashboard Cite

We aimed to evaluate the neuroprotective efficacy of rasagiline in pseudophakic patients who had surgery for macula-off rhegmatogenous retinal detachment (RRD). This was a 6-month, prospective, randomized, double-blind, placebo-controlled pilot study. Patients presenting with acute macula-off RRD were recruited and randomized 1:1 to receive rasagiline 1 mg/day or placebo for 7 days. Bestcorrected visual acuity (BCVA) and optical coherence tomography were acquired 1 day before as well as 2 days, 3 weeks, 3 months and 6 months after surgery. We screened 26 patients with RRD whereof 23 were eventually included and randomized. The primary outcome was final BCVA. Secondary outcomes included central retinal thickness (CRT) and adverse events (AE). We evaluated photoreceptor cells (prc) recovery through morphological measurements. The baseline characteristics were comparable between groups. BCVA significantly improved in both groups (letters gained: rasagiline 61.5 ± 18.1 vs placebo 55.3 ± 29.2, p = 0.56), but no significant inter-group difference was found at any visit. CRT was stable 3 weeks after surgery onwards, with no inter-group difference. No treatment-emergent AE occurred. Significant prc restoration was observed from 3 weeks to 6 months after surgery, without inter-group difference at either visit. Ellipsoid zone integrity (β = 0.517, p = 0.008) and foveal bulge (β = 0.387, p = 0.038) were significant predictors of good final BCVA. In conclusion, perioperative oral treatment with rasagiline 1 mg/day for 7 days did not show significant benefits on visual or anatomical outcomes in macula-off RRD patients. Rhegmatogenous retinal detachment (RRD) refers to separation of the neurosensory retina from the retinal pigment epithelium (RPE) due to accumulation of subretinal fluid through one or more retinal breaks 1. Currently, surgical repair is the only available treatment. Foveal detachment (macula-off) occurs in 54.5% of all RRD patients and is a major factor influencing visual recovery after successful surgical repair 2. As a result of deprived metabolic supply from the RPE and choroidal vasculature, photoreceptor (prc) death is the ultimate cause of vision loss after RRD 3. This is particularly relevant in the macula, where the density of prc is the highest and maximal visual acuity is achieved. Arguably, visual acuity recovery is significantly limited due to prc loss. Apoptosis was believed to be the major cause involved in prc death. However, recent evidence demonstrated that non-apoptotic forms of cell death (autophagy and necrosis), mitochondrial outer membrane permeabilization and inflammation raised by the interaction between dying cells and phagocytes all play a role in prc death after RRD 4. Accordingly, strategies targeting these pathways may be effective in prc rescue after RRD. Rasagiline [N-propargyl-1-(R)-aminoindan] is a second-generation propargylamine pharmacophore that selectively and irreversibly inhibits monoamine oxidase B (MAO-B). It has been an approved drug for the treatment of Parkinson's d...

show abstract

Vitreous Cytokine Expression and a Murine Model Suggest a Key Role of Microglia in the Inflammatory Response to Retinal Detachment

Cited by 39 publications

References 59 publications

Stimulation of Insulin Signaling Reverses Inflammation-Induced Cone Death in Retinal Detachment

Stimulation of Insulin Signaling Reverses Inflammation-Induced Cone Death in Retinal Detachment

Inflammatory and Fibrogenic Factors in Proliferative Vitreoretinopathy Development

Neuroprotection with rasagiline in patients with macula-off retinal detachment: A randomized controlled pilot study

Contact Info

Product

Resources

About