Assessment of Neurotrophins and Inflammatory Mediators in Vitreous of Patients With Diabetic Retinopathy

Abstract

PurposeTo assess vitreous levels of inflammatory cytokines and neurotrophins (NTs) in diabetic retinopathy (DR) and elucidate their potential roles.MethodsA prospective study was performed on 50 vitreous samples obtained from patients with DR (n = 22) and the nondiabetic controls (n = 28). All patients were candidates for vitrectomy. Inflammatory cytokine and NT levels were determined with ELISA. Potential source and role of NTs was determined by using human retinal Müller glia and mouse photoreceptor cells and challenging them with TNF-α or IL-1β, followed by detection of NTs and cell death.ResultsVitreous NT levels of all DR patients were significantly higher than those of nondiabetic controls (nerve growth factor [NGF, P = 0.0001], brain-derived neurotrophic factor [BDNF, P = 0.009], neurotrophin-3 [NT-3, P < 0.0001], neurotrophin-4 [NT-4, P = 0.0001], ciliary neurotrophic factor [CNTF, P = 0.0001], and glial cell–derived neurotrophic factor [GDNF, P = 0.008]). Similarly, the levels of inflammatory mediators IL-1β (P < 0.0001), IL-6 (P = 0.0005), IL-8 (P < 0.0001), and TNF-α (P < 0.0001) were also higher in eyes with DR. Interestingly, inflammatory cytokine and NT levels, particularly TNF-α (P < 0.05), IL-8 (P < 0.004), NT-3 (P = 0.012), NGF (P = 0.04), GDNF (P = 0.005), and CNTF (P = 0.002), were higher in eyes with nonproliferative diabetic retinopathy (NPDR) than in eyes with active proliferative diabetic retinopathy (PDR). Cytokine stimulation of Müller glia resulted in production of NTs, and GDNF treatment reduced photoreceptor cell death in response to inflammation and oxidative stress.ConclusionsTogether, our study demonstrated that patients with DR have higher levels of both inflammatory cytokines and NTs in their vitreous. Müller glia could be the potential source of NTs under inflammatory conditions to exert neuroprotection.

Sympathetic Effects of Internal Carotid Nerve Manipulation on Choroidal Vascularity and Related Measures

“…TNF-a upregulation is involved in many diseases as oxidative signaling in angiogenesis. 28 Upregulation of inflammatory cytokines such as TNF-a is implicated in the pathogenesis of DR. 29 As expected, we found that electrical stimulation of the ICN caused a temporary reduction in choroidal blood flow due to vasoconstriction, as well as mydriasis resulting from adrenergic effects on the iris dilator muscle. Other studies in rat have reported decreased uveal blood flow following acute cervical sympathetic trunk stimulation, an effect mediated exclusively by a 1 -ARs.…”

Potential of Müller Glia for Retina Neuroprotection

“…31 In addition, Müller glia is not only a source of neurotrophins within the retina but also respond to neurotrophins as they express all the neurotrophin receptors. 41 Release of neurotrophins from Müller glia can also be promoted by other neurotrophins, 42 inflammatory cytokines, 43 as well by activated microglia. 30 However, this response appears to be selective, as microglia conditioned media increases the Müller glia expression of mRNA coding for BDNF, but does not modify the expression of NGF, NT-3, CNTF.…”

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

“…Elevation in systemic and local chemokine concentration is present in patients suffering from DR (Petrovic et al, ; Koleva‐Georgieva et al, ; Suzuki et al, ). Several authors could demonstrate increased levels of TNF‐α, IL‐8, CCL2, IL‐1β, and IL‐6 in the vitreous fluid (Demircan et al, ; Murugeswari et al, ; Boss et al, ). Furthermore, peripheral monocytes from DR patients secrete high amounts of IL‐1β, IL‐6, TNF‐α, IL‐8, and IL‐1ra (Hatanaka et al, ; Bradshaw et al, ).…”