A model of progressive photo-oxidative degeneration and inflammation in the pigmented C57BL/6J mouse retina

Abstract

Light-induced degeneration in rodent retinas is an established model for of retinal degeneration, including the roles of oxidative stress and neuroinflammatory activity. In these models, photoreceptor death is elicited via photo-oxidative stress, and is exacerbated by recruitment of subretinal macrophages and activation of immune pathways including complement propagation. Existing light damage models have relied heavily on albino rodents, and mostly using acute light stimuli. These albino models have proven valuable in uncovering the pathogenic mechanisms of such pathways in the context of retinal disease. However, their inherent albinism hinders comparability to normal retinal physiology, and also makes gene technology analysis time-consuming due to the predominance of the pigmented mouse strains in these applications. In this study, we characterise a new light damage model utilising C57BL/6J mice over a 7 day period of chronic light exposure. We use high-efficiency LED technology to deliver a sustained intensity of 100 k lux with negligible modulation of ambient temperature. We show that in the C57BL/6J mouse, chronic light exposure elicits the cardinal features of light damage including photoreceptor degeneration, atrophy of the choriocapillaris, decreased retinal function and increases in oxidative stress markers 4-HNE and 8-OHG, which emerge progressively over the 7 day period of exposure. These changes are accompanied by robust recruitment of IBA1+ and F4/80 + microglia/macrophages to the ONL and subretinal space, followed the strong up-regulation of monocyte-chemoattractants Ccl2, Ccl3, and Ccl12, as well as increases in expression of complement component C3. These findings are in agreement with prior damage models conducted in albino rodents such as Balb/c mice, and support the use of this new model in further investigating the causative features of oxidative stress and inflammation in retinal disease.

Complement Components Showed a Time-Dependent Local Expression Pattern in Constant and Acute White Light-Induced Photoreceptor Damage

“…Perhaps LD-dependent complement expression is different in murine and rat retina. This hypothesis is supported by novel data of the same group showing, that for pigmented light treated mice c3 mRNA expression decreases after a peak expression at d5 again in contrast to c3 expression in rats (Rutar et al, 2011; Natoli et al, 2016)…”

Retinal metabolic events in preconditioning light stress as revealed by wide-spectrum targeted metabolomics

“…Although there is no clear direct evidence that light causes irreparable retinal degradation over a human being’s lifetime, it is widely believed that oxidative stress and activation of the immune system caused by long-term exposure to moderate light, in addition to ageing (i.e. metabolic and circulatory changes, and immune-senescence) can lead to progressive tissue damage in the retina (Natoli et al 2016; Organisciak et al 1998; Penn and Anderson 1987; Rutar et al 2011, 2012; Youssef et al 2011). Retina’s prior light-experience (so-called ‘light history’) has been shown to be essential for determining its sensitivity to subsequent acute light damage, suggesting that retinal cells may acclimate to their environment thereby maximizing their ability to survive on the long-term (Organisciak et al 1998; Penn and Anderson 1991).…”

Taurine Depletion Causes ipRGC Loss and Increases Light-Induced Photoreceptor Degeneration

“…1 Previous studies have shown that b-alanine treatment administered in the drinking water at a concentration of 3% causes a decline in taurine plasma levels [34][35][36] and in tissues such as the hippocampus, posterior cortex, and retina, as well as in cellular taurine content 13,14,[37][38][39][40] and also that taurine depletion causes loss of retinal neurons 6,41-43 (see below). [50][51][52] Light is a risk factor for some retinal degenerations, [53][54][55][56] and it accelerates photoreceptor degeneration in some inherited retinal degenerations. 54,[57][58][59] In previous work, [18][19][20]50 we documented that light exposure causes rapid photoreceptor degeneration and, longterm, alterations in all the retinal layers and RGC loss.…”