Marrow-Derived Cells Regulate the Development of Early Diabetic Retinopathy and Tactile Allodynia in Mice

Abstract

The hypothesis that marrow-derived cells, and specifically proinflammatory proteins in those cells, play a critical role in the development of diabetes-induced retinopathy and tactile allodynia was investigated. Abnormalities characteristic of the early stages of retinopathy and allodynia were measured in chimeric mice lacking inducible nitric oxide synthase (iNOS) or poly(ADP-ribosyl) polymerase (PARP1) in only their marrow-derived cells. Diabetes-induced capillary degeneration, proinflammatory changes, and superoxide production in the retina and allodynia were inhibited in diabetic animals in which iNOS or PARP1 was deleted from bone marrow cells only. Of the various marrow cells, neutrophils (and monocytes) play a major role in retinopathy development, because retinal capillary degeneration likewise was significantly inhibited in diabetic mice lacking the receptor for granulocyte colony-stimulating factor in their marrow-derived cells. Immunodepletion of neutrophils or monocytes inhibited the endothelial death otherwise observed when coculturing leukocytes from wild-type diabetic animals with retinal endothelium. iNOS and PARP1 are known to play a role in inflammatory processes, and we conclude that proinflammatory processes within marrow-derived cells play a central role in the development of diabetes complications in the retina and nerve.

Photoreceptor Cells Influence Retinal Vascular Degeneration in Mouse Models of Retinal Degeneration and Diabetes

“…Unlike what is seen in diabetes, 21,34,36,37,47,49–52 markers of inflammation showed no consistent increase in either model of photoreceptor cell degeneration at the durations of diabetes studied, thus providing no evidence that they play a role in the retinal capillary degeneration manifested in these models.…”

Retinylamine Benefits Early Diabetic Retinopathy in Mice

“…6) was due solely to this modest loss of photoreceptors compared with that in WT mice. We have implicated leukocytes as contributing to the development of DR (39 -41, 46), and killing of retinal endothelial cells has been demonstrated with leukocytes from both diabetic patients (46) and animals (41). We isolated the leukocyte fraction from the blood of animals in the various experimental groups and assessed the effects of in vivo Ret-NH 2 treatment on both basal superoxide generation by these leukocytes and leukocyte-mediated killing of retinal endothelial cells.…”

“…A contribution of white blood cells to the pathogenesis of DR was suggested initially by evidence that diabetes-induced degeneration of retinal capillaries was significantly reduced in mice deficient in CD18 or ICAM-1 (52). The idea was further supported in mice wherein the interaction of leukocytes with endothelial adhesion molecules was blocked by neutrophil inhibitory factor (39) or mice wherein several proteins involved in inflammation or oxidative stress were deleted selectively from myeloid-derived cells (40,41). Such leukocytemediated damage to the vascular endothelial cells in diabetes has been replicated ex vivo in a co-culture system where leukocytes from diabetic or nondiabetic mice or patients were incubated with retinal endothelial cells (39,41,46).…”

“…The idea was further supported in mice wherein the interaction of leukocytes with endothelial adhesion molecules was blocked by neutrophil inhibitory factor (39) or mice wherein several proteins involved in inflammation or oxidative stress were deleted selectively from myeloid-derived cells (40,41). Such leukocytemediated damage to the vascular endothelial cells in diabetes has been replicated ex vivo in a co-culture system where leukocytes from diabetic or nondiabetic mice or patients were incubated with retinal endothelial cells (39,41,46). Leukocytes can damage retinal endothelial cells and vasculature by releasing small lipids such as leukotrienes (35,40,62).…”

Fractalkine Signaling Attenuates Perivascular Clustering of Microglia and Fibrinogen Leakage during Systemic Inflammation in Mouse Models of Diabetic Retinopathy

“…Growing evidence suggests neuroinflammation plays an early role in mediating neuronal and vascular pathology in DR (Zheng et al, 2007; Tang and Kern, 2011; Li et al, 2012). Microglia, which are normally engaged with neurons and taking part in synaptic maintenance and clearance of cellular debris (Sierra et al, 2010; Paolicelli et al, 2011), are now recognized as being more than just intrinsic “bystanders”, but immune cells with key roles in injury and repair.…”