Anti-Inflammatory Role of Netrin-4 in Diabetic Retinopathy

Abstract

Diabetic retinopathy is characterized by dysfunction of the retinal vascular network, combined with a persistent low-grade inflammation that leads to vision-threatening complications. Netrin-4 (NTN4) is a laminin-related secreted protein and guidance cue molecule present in the vascular basal membrane and highly expressed in the retina. A number of studies inferred that the angiogenic abilities of NTN4 could contribute to stabilize vascular networks and modulate inflammation. Analyzing human specimens, we show that NTN4 and netrin receptors are upregulated in the diabetic retina. We further evaluated a knock-out model for NTN4 undergoing experimental diabetes induced by streptozotocin. We investigated retina function and immune cells in vivo and demonstrated that NTN4 provides a protective milieu against inflammation in the diabetic retina and prevents cytokine production.

The neutrophil percentage‐to‐albumin ratio is related to the occurrence of diabetic retinopathy

“…Our findings were in line with those of other research reports that examined the prognostic significance of NPARs in various clinical scenarios, such as cardiogenic shock, 15 acute kidney injury, 16 myocardial infarction, 30 and rectal cancer 31 . Inflammation appears to be a significant factor contributing to the occurrence and progression of DR, according to several research reports 32,33 . Diabetic patients with DR have elevated levels of several inflammatory chemokines and cytokines in their blood as well as their ocular samples (aqueous and vitreous humor).…”

“… 31 Inflammation appears to be a significant factor contributing to the occurrence and progression of DR, according to several research reports. 32 , 33 Diabetic patients with DR have elevated levels of several inflammatory chemokines and cytokines in their blood as well as their ocular samples (aqueous and vitreous humor).…”

Effects of diabetes on microglial physiology: a systematic review of in vitro, preclinical and clinical studies

“…Administration of STZ to class A scavenger receptor deficient mice (Sr-a −/− ) results in a more severe version of diabetic retinopathy with increased inflammatory Vargas-Soria et al Journal of Neuroinflammation (2023) 20:57 markers, including F4/80 + and CD64 + retinal populations and larger increases of pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6 or MCP-1, favoring an increase in pJNK/total JNK and pIκB/total IκB ratios, whereas pERK/total ERK ratio is reduced [119]. STZ has also been administered to netrin-4 KO mice, a lamininrelated secreted protein and guidance molecule highly expressed in the basal membrane of the retinal vasculature which might contribute to vascular stabilization and modulate the inflammatory process [144]. Netrin-4 KO mice show a significantly higher number of amoeboidlike cells in the retina and STZ-induced diabetes contributes to maintaining this phenotype, accompanied by higher mRNA expression of ICAM-1, CCL-2 and IL-6, suggesting that netrin-4 KO mice have a more robust pro-inflammatory profile and that netrin-4 plays a protective role against inflammation in the diabetic retina [144].…”

“…STZ has also been administered to netrin-4 KO mice, a lamininrelated secreted protein and guidance molecule highly expressed in the basal membrane of the retinal vasculature which might contribute to vascular stabilization and modulate the inflammatory process [144]. Netrin-4 KO mice show a significantly higher number of amoeboidlike cells in the retina and STZ-induced diabetes contributes to maintaining this phenotype, accompanied by higher mRNA expression of ICAM-1, CCL-2 and IL-6, suggesting that netrin-4 KO mice have a more robust pro-inflammatory profile and that netrin-4 plays a protective role against inflammation in the diabetic retina [144]. The inflammatory response is also increased in diabetic mice lacking A2A adenosine receptor, showing a significant increase of TNF-α in the retina [134].…”

Relevance of Peptide Homeostasis in Metabolic Retinal Degenerative Disorders: Curative Potential in Genetically Modified Mice

“…In previous works, different neuropeptides have shown promising curative effects in all of the above-mentioned consequences of DR in the retina ( Wilkinson-Berka et al, 2019 ). Genetic models have made it possible to target the molecular processes of these retinal alterations or explore promising therapeutic pathways from different angles; they can highlight new causative events and/or prospective mediators in processes of inflammation ( Bogdanov et al, 2017 ; Sigurdardottir et al, 2019 ; Zapadka et al, 2020 ; Chen et al, 2021 ; Crespo-Garcia et al, 2021 ), vascular alterations ( Kern et al, 2010 ; Zhou et al, 2017 ; Zhu et al, 2018 ; Lindstrom et al, 2019 ; Sigurdardottir et al, 2019 ; Ivanova et al, 2020 ; Tecilazich et al, 2020 ), oxidative stress ( Kowluru et al, 2006 ; Bogdanov et al, 2017 ; Dierschke et al, 2019 ; Shao et al, 2019 ; Sigurdardottir et al, 2019 ; Chen et al, 2021 ), VEGF production ( Lin et al, 2011 ; Fu et al, 2015 ; Yin et al, 2021 ) and the formation of advanced glycation end products (or their receptor) and neuronal/glial cell degeneration ( Kezic et al, 2013 ; Yang et al, 2015 ; Chen et al, 2021 ). The contribution of pro-angiogenic VEGF isoforms to the pathomechanism of DR has also been explored using Ins2 Akita mice ( Bucolo et al, 2021 ).…”