Distinctive waves of innate immune response in the retina in experimental autoimmune encephalomyelitis

Cruz-Herranz, Andrés; Oertel, Frederike Cosima; Kim, Kicheol; Cantó, Ester; Timmons, Garrett; Sin, Jung Hyung; Devereux, Michael; Baker, Nicholas S.; Michel, Brady; Schubert, Ryan; Rani, Lakshmisahithi; Cordano, Christian; Baranzini, Sergio E.; Green, Ari J.

doi:10.1172/jci.insight.149228

Cited by 18 publications

(22 citation statements)

References 49 publications

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“…These data indicated that the retinae of both mouse strains participated in the inflammatory response despite the lack of inflammatory infiltrates from the systemic compartment. This observation was consistent with the idea of waves of resident innate immune cell activation in the retina during EAE that has been previously reported [ 14 ]. Notably, a decrease of neurotrophic factors (BDNF and CNTF) was apparent in the retina in the course of EAE, and the expression of both neurotrophic factors was below baseline in the recovery phase – again with similar dynamics in wild-type and Aqp4 –/– retinae (Supplementary Fig.…”

Section: Resultssupporting

confidence: 93%

“…However, the retinal thickness correlates with the inflammatory response in the CNS of EAE mice as well [ 9 ]. Since we did not detect inflammatory infiltrates in the retinae of either wild-type or Aqp4 –/– mice, it is possible that remote effects of the inflammatory process in the optic nerve or activation of resident innate immune cells [ 14 ] might trigger retinal swelling. The increase in retinal TNF RNA levels during EAE, which has also been shown previously [ 9 ], and the detection of Iba1 + cells are consistent with this concept and might correspond to the first wave of innate immune activation in the retina during EAE [ 14 ] – well before retrograde axonal degeneration occurs.…”

Section: Discussionmentioning

confidence: 99%

“…Since recent work by us and others reproduced key retinal findings from studies on MS patients in experimental autoimmune encephalomyelitis (EAE) [ 9 , 13 ], we explored the role of AQP4 in retinal pathology in the MOG(35–55)-induced EAE model, which involves the retina through innate immune activation [ 14 ]. We found that lack of AQP4 results in increased and sustained retinal thickness in longitudinal OCT analyses and enhanced albumin extravasation in Aqp4 –/– mice as compared with wild type control animals during EAE.…”

Section: Introductionmentioning

confidence: 99%

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Aquaporin-4 prevents exaggerated astrocytosis and structural damage in retinal inflammation

et al. 2022

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Aquaporin-4 (AQP4) is the molecular target of the immune response in neuromyelitis optica (NMO) that leads to severe structural damage in the central nervous system (CNS) and in the retina. Conversely, AQP4 might be upregulated in astrocytes as a compensatory event in multiple sclerosis. Thus, the functional relevance of AQP4 in neuroinflammation needs to be defined. Here, we tested the role of AQP4 in the retina in MOG(35–55)-induced experimental autoimmune encephalomyelitis (EAE) using optical coherence tomography (OCT), OCT angiography, immunohistology, flow cytometry, and gene expression analysis in wild-type and Aqp4–/– mice. No direct infiltrates of inflammatory cells were detected in the retina. Yet, early retinal expression of TNF and Iba1 suggested that the retina participated in the inflammatory response during EAE in a similar way in wild-type and Aqp4–/– mice. While wild-type mice rapidly cleared retinal swelling, Aqp4–/– animals exhibited a sustainedly increased retinal thickness associated with retinal hyperperfusion, albumin extravasation, and upregulation of GFAP as a hallmark of retinal scarring at later stages of EAE. Eventually, the loss of retinal ganglion cells was higher in Aqp4–/– mice than in wild-type mice. Therefore, AQP4 expression might be critical for retinal Müller cells to clear the interstitial space from excess vasogenic edema and prevent maladaptive scarring in the retina during remote inflammatory processes of the CNS. Key messages Genetic ablation of AQP4 leads to a functional derangement of the retinal gliovascular unit with retinal hyperperfusion during autoimmune CNS inflammation. Genetic ablation of AQP4 results in a structural impairment of the blood retina barrier with extravasation of albumin during autoimmune CNS inflammation. Eventually, the lack of AQP4 in the retina during an inflammatory event prompts the exaggerated upregulation of GFAP as a hallmark of scarring as well as loss of retinal ganglion cells.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Aquaporin-4 prevents exaggerated astrocytosis and structural damage in retinal inflammation

et al. 2022

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“…It has been associated with blood-brain barrier permeability, dysregulated T-cell activation and modulating effects on B-cells (13)(14)(15)(16)(17)(18)(19). Using non-invasive, in vivo confocal scanning laser ophthalmoscopy (cSLO), microglial activation can also be assessed in the retina of CX3CR1 GFP mice in the context of EAE (20).…”

Section: Introductionmentioning

confidence: 99%

Semi-Automated Live Tracking of Microglial Activation in CX3CR1GFP Mice During Experimental Autoimmune Encephalomyelitis by Confocal Scanning Laser Ophthalmoscopy

et al. 2021

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Confocal scanning laser ophthalmoscopy (cSLO) is a non-invasive technique for real-time imaging of the retina. We developed a step-by-step protocol for the semi-automatic evaluation of myeloid cells in cSLO images from CX3CR1GFP mice, expressing green fluorescent protein (GFP) under control of the endogenous CX3C chemokine receptor 1 locus. We identified cSLO parameters allowing us to distinguish animals with experimental autoimmune encephalomyelitis (EAE) from sham-treated/naïve animals. Especially cell count (CC) and the total microglial area (SuA) turned out to be reliable parameters. Comparing the cSLO results with clinical parameters, we found significant correlations between the clinical EAE score and the SuA and of the inner retinal layer thickness, measured by optical coherence tomography, with the CC as well as the SuA. As a final step, we performed immunohistochemistry to confirm that the GFP-expressing cells visualized by the cSLO are Iba1 positive and validated the step-by-step protocol against manual counting. We present a semi-automatic step-by-step protocol with a balance between fast data evaluation and adequate accuracy, which is optimized by the option to manually adapt the contrast threshold. This protocol may be useful for numerous research questions on the role of microglial polarization in models of inflammatory and degenerating CNS diseases involving the retina.

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“… 16 Moreover, recent in vivo data from myelin oligodendrocyte glycoprotein 35-55 experimental autoimmune encephalomyelitis showed a strong and dynamic microglial activation following optic neuritis (ON). 17 …”

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confidence: 99%

Retinal Hyperreflecting Foci Associate With Cortical Pathology in Multiple Sclerosis

Pengo

Miante

Franciotta

et al. 2022

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesMicroglia, the resident immune cell of the brain and retina, is widespread activated in the white and gray matter (GM) in multiple sclerosis (MS). The objective of this study is to evaluate the presence and number of hyperreflecting foci (HRF), considered clusters of activated and proliferating retinal microglia, and their association with clinical and radiologic disease parameters in relapsing-remitting MS (RRMS).MethodsAt baseline, 80 patients with RRMS underwent optical coherence tomography (OCT) and 3T-MRI (including 3-dimensional T1, fluid-attenuated inversion recovery, and double inversion recovery sequences), closed to their disease onset (6.3 ± 5.1 months). These patients were then clinically and radiologically followed up for a mean of 43 months, evaluating the no evidence of disease activity (NEDA) condition, further divided into clinical (cNEDA) and radiologic (rNEDA). Patients with a clinical history or MRI/OCT findings suggestive of optic neuritis (ON) were excluded from the study.ResultsCompared with healthy controls, the HRF number was significantly higher in the inner nuclear layer (INL) of patients with RRMS (19.55 ± 5.65 vs 13.84 ± 2.57, p < 0.001) and associated with INL volume (β: 1.21, p < 0.001). GM lesion volume significantly correlated with the INL HRF count (p = 0.008). Survival analysis revealed a significant association between INL HRF and both cNEDA (p = 0.017) and rNEDA (p = 0.002).DiscussionWe found a strong association between retinal microglial proliferation and cortical pathology in RRMS, a finding suggesting a possible underlying common immunopathologic mechanism. Furthermore, microglial activation at baseline was observed to predict subsequent inflammatory events, indicating that HRF might be a candidate prognostic biomarker worthy of further investigation.Classification of EvidenceThis study provides Class II evidence that in patients with early RRMS but without ON, the number of HRF on OCT of the retinal inner nuclear layer is associated with cNEDA and rNEDA.

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Distinctive waves of innate immune response in the retina in experimental autoimmune encephalomyelitis

Cited by 18 publications

References 49 publications

Aquaporin-4 prevents exaggerated astrocytosis and structural damage in retinal inflammation

Aquaporin-4 prevents exaggerated astrocytosis and structural damage in retinal inflammation

Semi-Automated Live Tracking of Microglial Activation in CX3CR1GFP Mice During Experimental Autoimmune Encephalomyelitis by Confocal Scanning Laser Ophthalmoscopy

Retinal Hyperreflecting Foci Associate With Cortical Pathology in Multiple Sclerosis

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