Profibrotic cytokines in aqueous humour correlate with aqueous flare in patients with rhegmatogenous retinal detachment

Hoerster, Robert; Hermann, Manuel M.; Rosentreter, André; Muether, Philipp S.; Kirchhof, Bernd; Fauser, Sascha

doi:10.1136/bjophthalmol-2012-302636

Cited by 43 publications

(48 citation statements)

References 22 publications

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“…In our experiments, retinal IL6 protein expression was undetectable following retinal detachment (Table 1; Additional file 4: Figure S2a), which is consistent with RNAseq data showing low IL6 gene expression [18]. These results suggest that although high levels of IL6 are evident in human samples of aqueous humor [7], vitreous [9] and subretinal fluid [7–9], it is apparently not secreted by the retina, but rather by invasive cells [10] in the vitreous.…”

Section: Discussionsupporting

confidence: 88%

“…PVR is triggered by a cytokine storm, including MCP-1/CCL2 [7], IL6 [7–9], ICAM-1 [8], and TIMP-1 [9]. One common pro-inflammatory cytokine implicated in PVR, as well as the acute phase response of many inflammatory diseases, is interleukin 6 (IL6).…”

Section: Introductionmentioning

confidence: 99%

“…One common pro-inflammatory cytokine implicated in PVR, as well as the acute phase response of many inflammatory diseases, is interleukin 6 (IL6). Secreted by T cells, dendritic cells and macrophages, IL6 is significantly elevated in the vitreous [9, 10], aqueous humor [7] and subretinal fluid [7–9] of PVR patients in a manner correlated with the extent of the RD [9]. IL6 receptors consist of subunit α (IL6Rα) and subunit β (gp130, also known as IL6Rβ and CD130), a signal transducer also shared by many other cytokines.…”

Section: Introductionmentioning

confidence: 99%

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Rapid monocyte infiltration following retinal detachment is dependent on non-canonical IL6 signaling through gp130

Wang

Miller

Goswami

et al. 2017

J Neuroinflammation

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BackgroundRetinal detachment (RD) can lead to proliferative vitreoretinopathy (PVR), a leading cause of intractable vision loss. PVR is associated with a cytokine storm involving common proinflammatory molecules like IL6, but little is known about the source and downstream signaling of IL6 and the consequences for the retina. Here, we investigated the early immune response and resultant cytokine signaling following RD in mice.MethodsRD was induced in C57BL/6 J and IL6 knockout mice, and the resulting inflammatory response was examined using immunohistochemistry and flow cytometry. Cytokines and signaling proteins of vitreous and retinas were quantified by multiple cytokine arrays and Western blotting. To attempt to block IL6 signaling, a neutralizing antibody of IL6 receptor α (IL6Rα) or IL6 receptor β (gp-130) was injected intravitreally immediately after RD.ResultsWithin one day of RD, bone marrow-derived Cd11b + monocytes had extravasated from the vasculature and lined the vitreal surface of the retina, while the microglia, the resident macrophages of the retina, were relatively unperturbed. Cytokine arrays and Western blot analysis revealed that this sterile inflammation did not cause activation of IL6 signaling in the neurosensory retina, but rather only in the vitreous and aqueous humor. Monocyte infiltration was inhibited by blocking gp130, but not by IL6 knockout or IL6Rα blockade.ConclusionsTogether, our results demonstrate that monocytes are the primary immune cell mediating the cytokine storm following RD, and that any resulting retinal damage is unlikely to be a direct result of retinal IL6 signaling, but rather gp130-mediated signaling in the monocytes themselves. These results suggest that RD should be treated immediately, and that gp130-directed therapies may prevent PVR and promote retinal healing.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0886-6) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rapid monocyte infiltration following retinal detachment is dependent on non-canonical IL6 signaling through gp130

Wang

Miller

Goswami

et al. 2017

J Neuroinflammation

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“…[1516] However, reports about the relation of VEGF levels and redetachment rates are contradictory. [171819] Given the favorable results of the use of anti-VEGF agents in intraocular proliferative processes and the dilemma about an adjunct to surgical repair of retinal detachment to prevent PVR, this trial was designed to find if it is useful to add an anti-VEGF agent to the surgical protocol. Herein, the primary results are reported.…”

Section: Introductionmentioning

confidence: 99%

Intravitreal injection of bevacizumab in primary vitrectomy to decrease the rate of retinal redetachment: A randomized pilot study

Tousi

Hasanpour

Soheilian

2016

J Ophthalmic Vis Res

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Purpose:To evaluate the effect of intravitreal bevacizumab (IVB) as a surgical adjunct in prevention of proliferative vitreoretinopathy (PVR) after retinal detachment surgery.Methods:In this controlled, randomized pilot study, 27 patients with primary retinal detachment undergoing pars plana deep vitrectomy were included. Of these, 12 received IVB at the end of procedure. The anatomic success and best corrected visual acuity (BCVA) were compared to the control group at months 3 and 6 postoperatively.Results:At three month follow-up, 3 of 11 eyes (27.3%) had detached retinas in the IVB group versus 6 of 12 (50.0%) in the control group (P = 0.40). At six-month follow-up, 3 of 10 eyes (30%) had detached retinas in the IVB group versus 3 in 8 (37.5%) in the control group (P > 0.99). Mean logMAR BCVA improved significantly in both groups relative to baseline, but did not show a significant difference at three-and six-month follow-ups between the two groups.Conclusion:Our preliminary results show neither a benefit nor any harm from intervention in both anatomic and visual outcomes. Our results support conducting additional studies to evaluate the effect of intravitreal bevacizumab on postoperative PVR.

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“…[1][2][3][4][5][6] In PVR, the RPE contributes to the wound healing response by undergoing epithelium-mesenchyme transition (EMT) with further transdifferentiation into myofibroblasts. [1][2][3][4][5][6] Although inflammatory factors, 7-9 cytokines, 10,11 growth factors, [12][13][14][15][16] and extracellular matrix [17][18][19] have been extensively studied for their roles in the development of PVR, [20][21][22][23][24][25][26][27][28] the detailed molecular mechanisms controlling the process of RPE transdifferentiation remain unclear.…”

mentioning

confidence: 99%

Inhibition of DNA Methylation and Methyl-CpG-Binding Protein 2 Suppresses RPE Transdifferentiation: Relevance to Proliferative Vitreoretinopathy

Barrón

Ishikawa

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: He S, Barron E, Ishikawa K, et al. Inhibition of DNA methylation and methyl-CpG-binding protein 2 suppresses RPE transdifferentiation: relevance to proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci. 2015;56:5579-5589. DOI:10.1167/ iovs.14-16258 PURPOSE. The purpose of this study was to evaluate expression of methyl-CpG-binding protein 2 (MeCP2) in epiretinal membranes from patients with proliferative vitreoretinopathy (PVR) and to investigate effects of inhibition of MeCP2 and DNA methylation on transforming growth factor (TGF)-b-induced retinal pigment epithelial (RPE) cell transdifferentiation. METHODS.Expression of MeCP2 and its colocalization with cytokeratin and a-smooth muscle actin (a-SMA) in surgically excised PVR membranes was studied using immunohistochemistry. The effects of 5-AZA-2 0 -deoxycytidine (5-AZA-dC) on human RPE cell migration and viability were evaluated using a modified Boyden chamber assay and the colorimetric 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay. Expression of RASAL1 mRNA and its promoter region methylation were evaluated by real-time PCR and methylationspecific PCR. Effects of 5-AZA-dC on expression of a-SMA, fibronectin (FN), and TGF-b receptor 2 (TGF-b R2) and Smad2/3 phosphorylation were analyzed by Western blotting. Effect of short interfering RNA (siRNA) knock-down of MeCP2 on expression of a-SMA and FN induced by TGFb was determined.RESULTS. MeCP2 was abundantly expressed in cells within PVR membranes where it was double labeled with cells positive for cytokeratin and a-SMA. 5-AZA-dC inhibited expression of MeCP2 and suppressed RASAL1 gene methylation while increasing expression of the RASAL1 gene. Treatment with 5-AZA-dC significantly suppressed the expression of a-SMA, FN, TGF-b R2 and phosphorylation of Smad2/3 and inhibited RPE cell migration. TGF-b induced expression of a-SMA, and FN was suppressed by knock-down of MeCP2.CONCLUSIONS. MeCP2 and DNA methylation regulate RPE transdifferentiation and may be involved in the pathogenesis of PVR.

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Profibrotic cytokines in aqueous humour correlate with aqueous flare in patients with rhegmatogenous retinal detachment

Abstract: Laser flare photometry allows simple risk estimation for later PVR development. Elevated laser flare values correspond to an altered profibrotic intraocular cytokine milieu. These factors therefore constitute promising targets for a prophylactic intervention.

Cited by 43 publications

References 22 publications

Rapid monocyte infiltration following retinal detachment is dependent on non-canonical IL6 signaling through gp130

Rapid monocyte infiltration following retinal detachment is dependent on non-canonical IL6 signaling through gp130

Intravitreal injection of bevacizumab in primary vitrectomy to decrease the rate of retinal redetachment: A randomized pilot study

Inhibition of DNA Methylation and Methyl-CpG-Binding Protein 2 Suppresses RPE Transdifferentiation: Relevance to Proliferative Vitreoretinopathy

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