Inhibition of Caspase-1/Interleukin-1β Signaling Prevents Degeneration of Retinal Capillaries in Diabetes and Galactosemia

Abstract

The proinflammatory cytokine, interleukin (IL)-1␤, is known to induce vascular dysfunction and cell death. We investigated the role of IL-1␤ and caspase-1 (the enzyme that produces it) in diabetes-induced degeneration of retinal capillaries. Caspase-1 activity is increased in retinas of diabetic and galactosemic mice and diabetic patients. First, we investigated the effect of agents known to inhibit caspase-1 (minocycline and tetracycline) on IL-1␤ production and retinal capillary degeneration in diabetic and galactose-fed mice. Second, we examined the effect of genetic deletion of the IL-1␤ receptor on diabetes-induced caspase activities and retinal capillary degeneration. Diabetic and galactose-fed mice were injected intraperitoneally with minocycline or tetracycline (5 mg/kg). At 2 months of diabetes, minocycline inhibited hyperglycemia-induced caspase-1 activity and IL-1␤ production in the retina. Long-term administration of minocycline prevented retinal capillary degeneration in diabetic (6 months) and galactose-fed (13 months) mice. Tetracycline inhibited hyperglycemia-induced caspase-1 activity in vitro but not in vivo. Mice deficient in the IL-1␤ receptor were protected from diabetes-induced caspase activation and retinal pathology at 7 months of diabetes. These results indicate that the caspase-1/IL-1␤ signaling pathway plays an important role in diabetes-induced retinal pathology, and its inhibition might represent a new strategy to inhibit capillary degeneration in diabetic retinopathy. Diabetes

Fenofibric acid prevents retinal pigment epithelium disruption induced by interleukin-1β by suppressing AMP-activated protein kinase (AMPK) activation

“…Pro-inflammatory cytokines such as IL-1β play a crucial role in the pathogenesis of both PDR and DMO [19][20][21][22]. Apart from its intrinsic deleterious effect, IL-1β has been shown to stimulate several pro-inflammatory cytokines such as IL-6, IL-8 and monocyte chemotactic protein 1 (MCP-1) [26,27], which, in turn, have also been involved in both PDR and DMO [28][29][30].…”

“…In fact, treatment of RPE cells with either serum, interferon-γ, tumour necrosis factor-α, hepatocyte growth factor (HGF), IL-1β or placental growth factor-1 (PLGF-1) increases permeability and alters the levels or content of tight junction molecules [14][15][16][17][18]. As IL-1β plays an essential role in the development of DR [19][20][21][22], we decided to use this cytokine to provoke the breakdown of the RPE cell monolayer and to test the potential preventive effects of fenofibrate.…”

siah-1 Protein Is Necessary for High Glucose-induced Glyceraldehyde-3-phosphate Dehydrogenase Nuclear Accumulation and Cell Death in Müller Cells

“…Following treatment, cytosolic lysates were generated as previously described by us (4,16,44). Whole cell lysates were generated in 200 l of whole cell lysis buffer (50 mM HEPES, pH 7.5, 1% Triton X-100, 150 mM NaCl, 1 mM EDTA, and protease inhibitors 0.2 mM phenylmethylsulfonyl fluoride and 1 M leupeptin) and sonicated for 15 s. The protein concentrations were determined using the Bradford assay.…”

Nuclear GAPDH: changing the fate of Müller cells in diabetes

“…High glucose induces the production of various acute-phase cytokines [21][22][23][24][25][26]. In the Müller cells, high glucose activates caspase-1 which catalyzes the production of mature, active IL-1β from pro IL-1β and IL-18 [68].…”

“…Hyperglycemia also induces the production of pro-inflammatory cytokines by Müller cells. Thus, Müller cells are a potent source for pro-inflammatory cytokines and might play a crucial role in retinal inflammation associated with the development of diabetic retinopathy [21][22][23][24][25][26]. Cytokine secretion by Müller cells influences function and viability of surrounding retinal cells, such as the retinal endothelial cells, in a paracrine fashion and their own function and viability in an autocrine manner [22].…”