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Peripheral monocytes and neutrophils promote photoreceptor cell death in an experimental retinal detachment model.

ABSTRACT: Photoreceptor cell death and immune cell infiltration are two major events that contribute to retinal degeneration. However, the relationship between these two events has not been well delineated, primarily because of an inadequate understanding of the immunological processes involved in photoreceptor degeneration, especially that of peripheral leukocytes that infiltrate the subretinal space and retinal tissues. In this work, we characterized the role of leukocyte infiltration within the detached retina. We observed that CD45⁺ CD11b⁺ Ly6G⁺ neutrophils and CD45⁺ CD11b⁺ Ly6G^- Ly6C⁺ monocytes are the predominant peripheral immune cell populations that infiltrate the retinal and subretinal space after detachment. Selective depletion of monocytes or neutrophils using cell-specific targeting is neuroprotective for photoreceptors. These results indicate that peripheral innate immune cells contribute to photoreceptor degeneration, and targeting these immune cell populations could be therapeutic during retinal detachment.

SUBMITTER: Maidana DE

PROVIDER: S-EPMC10724298 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Peripheral monocytes and neutrophils promote photoreceptor cell death in an experimental retinal detachment model.

Maidana Daniel E DE Gonzalez-Buendia Lucia L Pastor-Puente Sara S Naqvi Afsar A Paschalis Eleftherios E Kazlauskas Andrius A Miller Joan W JW Vavvas Demetrios G DG

Cell death & disease 20231216 12

Photoreceptor cell death and immune cell infiltration are two major events that contribute to retinal degeneration. However, the relationship between these two events has not been well delineated, primarily because of an inadequate understanding of the immunological processes involved in photoreceptor degeneration, especially that of peripheral leukocytes that infiltrate the subretinal space and retinal tissues. In this work, we characterized the role of leukocyte infiltration within the detache ...[more]

PMID: 38102109

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Project description:Retinal detachment is a sight-threatening disorder, which occurs when the photoreceptors are separated from their vascular supply. The aim of the present study was to shed light on photoreceptor energy metabolism during experimental detachment in rats. Retinal detachment was induced in the eyes of rats via subretinal injection of sodium hyaluronate. Initially, we investigated whether detachment caused hypoxia within photoreceptors, as evaluated by the exogenous and endogenous biomarkers pimonidazole and HIF-1α, as well as by qPCR analysis of HIF target genes. The results showed no unequivocal staining for pimonidazole or HIF-1α within any detached retina, nor upregulation of HIF target genes, suggesting that any reduction in pO2 is of insufficient magnitude to produce hypoxia-induced covalent protein adducts or HIF-1α stabilisation. Subsequently, we analysed expression of cellular bioenergetic enzymes in photoreceptors during detachment. We documented loss of mitochondrial, and downregulation of glycolytic enzymes during detachment, indicating that photoreceptors have reduced energetic requirements and/or capacity. Given that detachment did not cause widespread hypoxia, but did result in downregulated expression of bioenergetic enzymes, we hypothesised that substrate insufficiency may be critical in terms of pathogenesis, and that boosting metabolic inputs may preserve photoreceptor bioenergetic production and, protect against their degeneration. Thus, we tested whether supplementation with the bioavailable energy substrate pyruvate mitigated rod and cone injury and degeneration. Despite protecting photoreceptors in culture from nutrient deprivation, pyruvate failed to protect against apoptotic death of rods, loss of cone opsins, and loss of inner segment mitochondria, in situ, when evaluated at 3 days after detachment. The regimen was also ineffective against cumulative photoreceptor deconstruction and degeneration when evaluated after 4 weeks. Retinal metabolism, particularly the bioenergetic profiles and pathological responses of the various cellular subtypes still presents a considerable knowledge gap that has important clinical consequences. While our data do not support the use of pyruvate supplementation as a means of protecting detached photoreceptors, they do provide a foundation and motivation for future research in this area.

Project description:PurposePhotoreceptor (PR) death is the ultimate cause of irreversible vision loss in retinal detachment (RD). Previous studies have shown that microglia may have a dual role in RD. Nevertheless, the potential protective effects of microglia on PR are largely unknown. We aimed to uncover the phagocytic role of microglia in RD and propose a new concept to regulate PR survival.MethodsAn RD model was conducted by injecting sodium hyaluronate into the subretinal space (SRS) of C57BL/6J wild type mice. Bioinformatics analysis was used to evaluate the highly enriched pathways and terms relating to phagocytosis in human datasets and mouse transcriptomes of RD. The observation of microglial morphology was performed by immunofluorescence through cryosection and flat mount. PLX 3397 was used for microglial ablation. Phagocytosis of the outer segment (OS) by microglia was confirmed by immunofluorescence and hematoxylin and eosin staining. Expression of phagocytic markers in microglia was detected by immunofluorescence of cryosection. The PR survival was measured by TUNEL assay and hematoxylin and eosin staining. The optical coherence tomography (OCT) images through the center of the fovea in twelve patients were obtained to observe the clinic features of IS/OS dynamics after RD.ResultsThe results showed that OS went through an accumulation-clearance process after RD. Ameboid microglia accumulated in the SRS and engulfed OS. Upregulation of phagocytic markers was observed in subretinal microglia. Depletion of microglia led to failure of OS clearance and retinal ruffling, which had the same characteristics as outer retinal undulation (ORU) in some patients with RD. PR did not benefit from microglial depletion, as no morphology and thickness recovery of PR was observed in the long term.ConclusionsThese results elucidate that microglial phagocytosis of OS is a critical process after RD. Insufficient phagocytosis leads to the accumulation of OS in the SRS and PR abnormalities. Appropriate regulation of microglial phagocytosis to remove OS may be a new concept to regulate photoreceptor survival.

Project description:Retinal detachment (RD) occurs in several major retinal conditions and often causes irreversible vision loss due to photoreceptor cell death. Retinal residential microglial cells are activated following RD and participate in photoreceptor cell death via direct phagocytosis and the regulation of inflammatory responses. Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor exclusively expressed on microglial cells in the retina, and has been reported to affect microglial cell homeostasis, phagocytosis and inflammatory responses in the brain. In this study, increased expression of multiple cytokines and chemokines in the neural retina was observed starting at 3 h following RD. Trem2 knockout (Trem2-/-) mice exhibited significantly more photoreceptor cell death than wild-type controls at 3 days after RD, and the number of TUNEL positive photoreceptor cells progressively decreased from day 3 to day 7 post-RD. A significant thinning of the outer nuclear layer (ONL), with multiple folds was observed in the Trem2-/- mice at 3 days post-RD. Trem2 deficiency reduced microglial cell infiltration and phagocytosis of stressed photoreceptors. There were more neutrophils in Trem2-/- retina following RD than in controls. Using purified microglial cells, we found Trem2 knockout is associated with increased CXCL12 expression. The aggravated photoreceptor cell death was largely reversed by blocking the CXCL12-CXCR4 mediated chemotaxis in Trem2-/- mice after RD. Our findings suggested that retinal microglia are protective in preventing further photoreceptor cell death following RD by phagocytosing presumably stressed photoreceptor cells and by regulating inflammatory responses. TREM2 is largely responsible for such protective effect and CXCL12 plays an important role in regulating neutrophil infiltration after RD. Collectively, our study pinpointed TREM2 as a potential target of microglial cells to ameliorate RD-induced photoreceptor cell death.

Dataset Information

Peripheral monocytes and neutrophils promote photoreceptor cell death in an experimental retinal detachment model.

Publications

Peripheral monocytes and neutrophils promote photoreceptor cell death in an experimental retinal detachment model.

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