Inflammation and N-formyl peptide receptors mediate the angiogenic activity of human vitreous humour in proliferative diabetic retinopathy

Abstract

This study provides evidence that inflammation mediates the angiogenic activity of PDR vitreous and paves the way for the development of FPR-targeting anti-inflammatory/anti-angiogenic approaches for PDR therapy.

Diabetic Retinopathy in the Spontaneously Diabetic Torii Rat: Pathogenetic Mechanisms and Preventive Efficacy of Inhibiting the Urokinase-Type Plasminogen Activator Receptor System

“…Inflammatory molecules may induce Müller cell gliosis, as evidenced by increased GFAP expression, and gliotic Müller cells express a wide variety of inflammatory factors, including cytokines [ 43 ]. In addition, UPARANT anti-inflammatory activity participates to the inhibition of the angiogenic phenotype by endothelial cells in response to the vitreous fluid from patients with proliferative DR, which is characterized by high levels of angiogenic and inflammatory factors [ 44 ]. Moreover, UPARANT action as an anti-inflammatory drug has been recently demonstrated in animal models of inflammation [ 45 ].…”

The Urokinase Receptor-Derived Peptide UPARANT Recovers Dysfunctional Electroretinogram and Blood–Retinal Barrier Leakage in a Rat Model of Diabetes

“…This is in line with the finding that UPARANT counteracts the inflammatory and proangiogenic effects of the vitreous fluid from patients with proliferative DR, which contains high levels of several inflammatory and angiogenic factors. 22,53 In this respect, UPARANT inhibition of inflammation may have vascular benefits in DR much greater than most anti-VEGF therapies intended to regulate the vascular changes mediated by VEGF action without substantially intervening on inflammatory events. 54 Consistently, an important role of antiinflammatory agents against the development and progression of DR lesions has been recently acknowledged.…”

The G‐protein‐coupled chemoattractant receptor Fpr2 exacerbates neuroglial dysfunction and angiogenesis in diabetic retinopathy

“…# indicates significantly (p < .05) decreased intensity in Db Fpr2 −/− mouse retinas compared with Db WT mouse retinas of human FPRs in the regulation of innate immune responses, inflammation, and angiogenesis in the eye. 21 Fpr2 was also shown to mediate Aβ1-42 activation of glial cells in the brain to exacerbate proinflammatory responses in the brain of Alzheimer's disease (AD). 39 Thus, Fpr2 in glial cells, which is upregulated by a number of proinflammatory stimulants including TLRs and inflammatory cytokines and furthermore, by high glucose, plays an important role in neuroglial disease conditions including AD, DR, and OIR.…”

“…20 It is also reported that Fpr2 mediates inflammation and angiogenesis in PDR vitreous in response to peptide agonists, suggesting the receptor as a target for PDR therapy. 21 Our previous study revealed that Fpr2 on Müller glial cells was upregulated by high glucose and participated in the pathological process of DR. 22 This promoted us to further examine the role of Fpr2 in two models of DR, one recapitulating the early vascular and neuroglial degenerative stage and the other representing the ischemia-induced neovascular stage. Here we report that Fpr2 accelerates neuroglial and vascular degeneration culminating in neovascularization.…”