Bone marrow-CNS connections: Implications in the pathogenesis of diabetic retinopathy

Abstract

Diabetic retinopathy is the fourth most common cause of blindness in adults. Current therapies, including anti-VEGF therapy, have partial efficacy in arresting the progression of proliferative diabetic retinopathy and diabetic macular edema. This review provides an overview of a novel, innovative approach to viewing diabetic retinopathy as the result of an inflammatory cycle that affects the bone marrow (BM) and the central and sympathetic nervous systems. Diabetes associated inflammation may be the result of BM neuropathy which skews haematopoiesis towards generation of increased inflammatory cells but also reduced production of endothelial progenitor cells responsible for maintaining healthy endothelial function and renewal. The resulting systemic inflammation further impacts the hypothalamus, promoting insulin resistance and diabetes, and initiates an inflammatory cascade that adversely impacts both macrovascular and microvascular complications, including diabetic retinopathy (DR). This review examines the idea of using anti-inflammatory agents that cross not only the blood-retinal barrier to enter the retina but also have the capability to target the central nervous system and cross the blood-brain barrier to reduce neuroinflammation. This neuroinflammation in key sympathetic centers serves to not only perpetuate BM pathology but promote insulin resistance which is characteristic of type 2 diabetic patients (T2D) but is also seen in T1D. A case series of morbidly obese T2D patients with retinopathy and neuropathy treated with minocycline, a well-tolerated antibiotic that crosses both the blood-retina and blood-brain barrier is presented. Our results indicates that minocycine shows promise for improving visual acuity, reducing pain from peripheral neuropathy, promoting weight loss and improving blood pressure control and we postulate that these observed beneficial effects are due to a reduction of chronic inflammation.

CX3CR1 deficiency accelerates the development of retinopathy in a rodent model of type 1 diabetes

“…The contribution of bone marrow-derived cells to the acceleration of retinopathy is well established [45]. We also have shown that diabetes skews hematopoiesis towards the generation of more pro-inflammatory monocytes, fewer anti-inflammatory monocytes and lower numbers of reparative progenitor cells [15–19]. Bone marrow progenitors from diabetic mice generate higher numbers of myeloid colonies, which is attributed to increased levels of M-CSF and inflammatory cytokines such as IL-1β, IL-27 and IFN-γ in the bone marrow microenvironment [17].…”

“…In contrast, classical pro-inflammatory Ly6C hi /CCR2 + monocytes lack CX3CR1 expression. We have consistently shown that diabetes skews hematopoiesis towards a myeloid phenotype with an increased infiltration of inflammatory CCR2 + monocytes in the retina [15–19]. …”

Dietary Compound Chrysin Inhibits Retinal Neovascularization with Abnormal Capillaries in db/db Mice

“…Acellular capillaries are a pathologic result typical of the loss of both pericytes and endothelial cells in diabetic retina, and their quantification is a useful way to assess the extent of retinopathy [34]. This study further determined whether chrysin blocked the formation of acellular capillaries in trypsin digested retina of db/db mice.…”

Advances in bone marrow stem cell therapy for retinal dysfunction

“…Similarly, in eyes with diabetic retinopathy, progressive loss of endothelial cells and pericytes leads to formation of naked basement membrane tubes. These naked basement tubes become acellular capillaries with irreversible retinal ischemia (Douglas et al, 2012). Thus, there is likely a limited window of opportunity for stem cell treatment to reverse or limit the structural damage within the retina.…”

“…circulating endothelial progenitor cells, was found to be defective due to a diabetes-associated reduction in phosphorylation and intracellular redistribution of vasodilator-stimulated phosphoprotein (VASP), an actin motor protein required for cell migration (LiCalzi et al, 2008). In fact, a defect in the migration of circulating endothelial progenitor cells might contribute to the development of diabetic retinopathy and other disorders (Douglas et al, 2012). Recent studies have shown that bone marrow-derived circulating pro-inflammatory monocytes are increased in diabetes while circulating endothelial progenitor cells (also called circulating angiogenic cells) are trapped in the bone marrow (Hazra et al 2013; Chakravarthy et al, 2016).…”