Optic nerve as a source of activated retinal microglia post-injury

Heuss, Neal D.; Roehrich, Heidi; McPherson, Scott W.; Gram, Andrea; L, Li; Gregerson, Dale S.

doi:10.1186/s40478-018-0571-8

Cited by 43 publications

(40 citation statements)

References 69 publications

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“…Recent studies reported that the activation of microglia in optic nerves can damage RGCs and axons in experimental glaucoma [28,29], and the activation of the Nrf2/HO-1 system can inhibit microglial activation [30,31]. The role of Nrf2 in inhibiting microglial activation and the possible anti-inflammatory property of TRIOL in our previous study [19,20] strongly suggested that the inhibition of microglial activation by activating the Nrf2/HO-1 pathway may be involved in the neuroprotection of TRIOL.…”

Section: Resultsmentioning

confidence: 99%

Marine-Steroid Derivative 5α-Androst-3β, 5α, 6β-triol Protects Retinal Ganglion Cells from Ischemia–Reperfusion Injury by Activating Nrf2 Pathway

Sheng

Chen

et al. 2019

Marine Drugs

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High intraocular pressure (IOP)-induced retinal ischemia leads to acute glaucoma, which is one of the leading causes of irreversible visual-field loss, characterized by loss of retinal ganglion cells (RGCs) and axonal injury in optic nerves (ONs). Oxidative stress and the inflammatory response play an important role in the ischemic injury of retinal and optic nerves. We focus on 5α-androst-3β, 5α, 6β-triol (TRIOL), a synthetic neuroactive derivative of natural marine steroids 24-methylene-cholest-3β, 5α, 6β, 19-tetrol and cholestane-3β, 5α, 6β-triol, which are two neuroactive polyhydroxysterols isolated from the soft coral Nephthea brassica and the gorgonian Menella kanisa, respectively. We previously demonstrated that TRIOL was a neuroprotective steroid with anti-inflammatory and antioxidative activities. However, the potential role of TRIOL on acute glaucoma and its underlying mechanisms remains unclear. Here, we report TRIOL as a promising neuroprotectant that can protect RGCs and their axons/dendrites from ischemic–reperfusion (I/R) injury in an acute intraocular hypertension (AIH) model. Intravitreal injection of TRIOL significantly alleviated the loss of RGCs and the damage of axons and dendrites in rats and mice with acute glaucoma. As NF-E2-related factor 2 (Nrf2) is one of the most critical regulators in oxidative and inflammatory injury, we further evaluated the effect of TRIOL on Nrf2 knockout mice, and the neuroprotective role of TRIOL on retinal ischemia was not observed in Nrf2 knockout mice, indicating that activation of Nrf2 is responsible for the neuroprotection of TRIOL. Further experiments demonstrated that TRIOL can activate and upregulate Nrf2, along with its downstream hemeoxygenase-1 (HO-1), by negative regulation of Kelch-like ECH (Enoyl-CoA Hydratase) associated Protein-1 (Keap1). In conclusion, our study shed new light on the neuroprotective therapy of retinal ischemia and proposed a promising marine drug candidate, TRIOL, for the therapeutics of acute glaucoma.

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Section: Resultsmentioning

confidence: 99%

Marine-Steroid Derivative 5α-Androst-3β, 5α, 6β-triol Protects Retinal Ganglion Cells from Ischemia–Reperfusion Injury by Activating Nrf2 Pathway

Sheng

Chen

et al. 2019

Marine Drugs

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“…At days 5 and 7 postinjury, these infiltrating monocytes/macrophages appeared to associate with GCL nerve fibers, suggesting that they were engulfing dying neurons. 41 , 42 Interestingly, Cdh5/td IR retinas did not show strong expression of td in microglia/macrophages but rather the vascular expression was augmented. The IR injury seemed to increase the Cdh5 promoter activity leading to a stronger tdTomato signal in the vasculature.…”

Section: Discussionmentioning

confidence: 98%

Utility of LysM-cre and Cdh5-cre Driver Mice in Retinal and Brain Research: An Imaging Study Using tdTomato Reporter Mouse

Fouda

Narayanan

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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The lysozyme 2 (Lyz2 or LysM) cre mouse is extensively used to achieve genetic manipulation in myeloid cells and it has been widely employed in retinal research. However, LysM has been recently described to be expressed in brain neurons and there is a debate on whether it is also expressed by resident microglia in addition to infiltrating macrophages. METHODS. We examined LysM-cre recombination in retinal tissue using a LysM-cre/ tdTomato reporter mouse together with immunolabeling for several retinal cell markers. We further compared LysM-cre tdTomato recombination with that of Cdh5-cre driver, which is expressed in both endothelial and hematopoietic cells. RESULTS. LysM-cre was strongly expressed in most microglia/resident macrophages in neonatal retinas (P8) and to a lesser extent in microglia of adult retinas. In addition, there was some neuronal recombination (8 %) of LysM-cre specifically in adult retinal ganglion cells and amacrine cells. After retinal ischemia-reperfusion injury, LysM-cre was strongly expressed in microglia/infiltrating macrophages. Cdh5-cre was expressed in endothelial and myeloid cells of P8 pups retinas. Unexpectedly, Cdh5 showed additional expression in adult mouse retinal ganglion cells and brain neurons. CONCLUSIONS. LysM-cre is expressed in macrophages and a subset of microglia together with a small but significant recombination of LysM-cre in the retinal neurons of adult mice. Cdh5 also showed some neuronal expression in both retina and brain of adult mice. These findings should be taken into consideration when interpreting results from central nervous system research using LysM-cre and Cdh5-cre mice.

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“…The optic nerve crush (ONC) injury was performed as described [32, 36, 41]. DSAEK forceps (Ambler Surgical, #2197E) provided a controlled injury to the optic nerve, consistently limiting the loss of retinal ganglion cells to approximately 50% [37].…”

Section: Methodsmentioning

confidence: 99%

“…More recently we reported in two injury models using CD11c DTR/GFP mice that the expanded retinal GFP hi cells were derived from microglia; appearing in response to the stress of cone photoreceptor degeneration in CD11 DTR/GFP × RPE65 −/− double transgenic mice [35] and in response to optic nerve injuries [37]. Results from ablation, parabiosis, fate-mapping, and optic nerve transection experiments showed that the GFP hi cells in the retina were not derived from the circulation, but were rather derived from resident retinal microglia and/or microglia recruited from the optic nerve.…”

Section: Introductionmentioning

confidence: 99%

“…Results from ablation, parabiosis, fate-mapping, and optic nerve transection experiments showed that the GFP hi cells in the retina were not derived from the circulation, but were rather derived from resident retinal microglia and/or microglia recruited from the optic nerve. In contrast to retinal microglia, many of the microglia from the optic nerve were also GFP + and Ki67 + [37]. These findings suggested that there were two niches of retinal innate immune cells; a relatively stable microglia niche and a specialized niche of microglia, as represented by the GFP hi cells in CD11c DTR/GFP mice, that can function as dendritic cells and whose numbers dynamically expand and contract in response to stimuli.…”

Section: Introductionmentioning

confidence: 99%

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The retinal environment induces microglia-like properties in recruited myeloid cells

McPherson

Heuss

Lehmann

et al. 2019

J Neuroinflammation

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Background Microglia are essential to the development of the CNS and its homeostasis. Our prior findings suggested a niche model to describe the behaviors of retinal microglia. Here, we ask whether new myeloid cells recruited to the retina are constrained to resemble endogenous microglia morphologically and functionally. Methods Use of CD11c DTR/GFP transgenic mouse allowed identification of two niches of retinal microglia distinguished by being GFP lo or GFP hi . We also used transgenic mice in which CX3CR1 + cells expressed YFP and were depletable following tamoxifen-induced expression of diphtheria toxin subunit A. We employed several ablation and injury stimulation protocols to examine the origin and fate of myeloid cells repopulating the retina. Analysis of retinal myeloid cells was done by microscopy, flow cytometry, and qRT-PCR. Results We found that the origin of new GFP hi and GFP lo myeloid cells in the retina of CD11c DTR/GFP mice, whether recruited or local, depended on the ablation and stimulation protocols. Regardless of origin, new GFP lo and GFP hi retinal myeloid cells were CD45 med CD11b + Ly6G − Ly6C lo Iba1 + F4/80 + , similar to endogenous microglia. Following tamoxifen-induced diphtheria toxin ablation, myeloid cell repopulation differed in the retina compared to the brain and optic nerve. Stimulation of replacement GFP hi cells was substantially attenuated in repopulating retinas after tamoxifen-induced diphtheria toxin ablation compared to control or radiation-ablated mice. In radiation bone marrow chimeric mice, replacement GFP hi myeloid cells from the circulation were slow to repopulate the retina unless stimulated by an optic nerve crush injury. However, once stimulated, recruited GFP hi cells were found to concentrate on injured retinal ganglion cells and were morphologically similar to GFP hi cells in non-ablated control CD11c DTR/GFP mice. Conclusions The results support the idea that GFP hi cells in the CD11c DTR/GFP mouse, whether recruited or from resident microglia, mark a unique niche of activated retinal myeloid cells. We conclude that the retinal environment has a potent influence on the function, morphology, and proliferative capacity of new myeloid cells regardless of their origin, compelling them to be equivalent to the endogenous microglia. Electronic supplementary materi...

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Optic nerve as a source of activated retinal microglia post-injury

Cited by 43 publications

References 69 publications

Marine-Steroid Derivative 5α-Androst-3β, 5α, 6β-triol Protects Retinal Ganglion Cells from Ischemia–Reperfusion Injury by Activating Nrf2 Pathway

Marine-Steroid Derivative 5α-Androst-3β, 5α, 6β-triol Protects Retinal Ganglion Cells from Ischemia–Reperfusion Injury by Activating Nrf2 Pathway

Utility of LysM-cre and Cdh5-cre Driver Mice in Retinal and Brain Research: An Imaging Study Using tdTomato Reporter Mouse

The retinal environment induces microglia-like properties in recruited myeloid cells

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