OMICs approaches-assisted identification of macrophages-derived MIP-1γ as the therapeutic target of botanical products TNTL in diabetic retinopathy

Abstract

Background: Inflammatory reaction in the dysfunction of retinal endotheliocytes has been considered to play a vital role in diabetic retinopathy (DR). Anti-inflammatory therapy so far gains poor outcome as DR treatment. This study aims to identify a novel therapeutic target of DR from the OMICs studies of a traditional anti-DR botanical products TNTL. Methods: Hyperglycemic mice were treated with TNTL. The anti-hyperglycemic effect of TNTL was validated to confirm the biological consistency of the herbal products from batches. Improvement of DR by TNTL was examined by various assays on the retina. Next-generation transcriptome sequencing and cytokine array was used to identify the therapeutic targets. In vitro study was performed to validate the target. Results: We observed that TNTL at its high doses possessed anti-hyperglycemic effect in murine type I diabetic model, while at its doses without reducing blood glucose, it suppressed DR incidence. TNTL restored the bloodretina barrier integrity, suppressed retinal neovascularization, and attenuated the retinal ganglion cell degeneration. Transcriptomic analysis on the retina tissue of hyperglycemic mice with or without TNTL revealed that the inflammatory retina microenvironment was significantly repressed. TNTL treatment suppressed pro-inflammatory macrophages in the retina, which resulted in the inactivation of endothelial cell migration, restoration of endothelial cell monolayer integrity, and prevention of leakage. Cytokine array analysis suggested that TNTL could significantly inhibit the secretion of MIP1γ from pro-inflammatory macrophages. Prevention of endothelial dysfunction by TNTL may be mediated by the inhibition of MIP1γ/CCR1 axis. More specifically, TNTL suppressed MIP1γ release from pro-inflammatory macrophages, which in turn inhibited the activation of CCR1-associated signaling pathways in endothelial cells. Conclusion: Our findings demonstrated that TNTL might be an alternative treatment to DR, and the primary source of potential drug candidates against DR targeting MIP1γ/CCR1 axis in the retinal microenvironment.

Protective Role of microRNA-200a in Diabetic Retinopathy Through Downregulation of PDLIM1

“… 4 During the development of DR, capillary nonperfusion would lead to increased pro-inflammatory factors because of retinal ischemia/hypoxia. Clear evidence from both DM animal models and clinical patients have demonstrated that inflammation plays an essential role in the pathogenesis of DR. 5 As reported in a previous study, it has been found that pro-inflammatory growth factors and cytokines, such as tumor necrosis factor alpha (TNFα), interleukin 6 (IL6), interleukin 1β (IL1β) and monocyte chemo-attractant protein-1 (MCP-1), are overexpressed in clinical samples of patients with DR. 6 Increased expression of inflammatory factors lead to BRB breakdown, and then damaged BRB is a key pathological progression in the incidence of macular edema. In a later stage of DR, angiogenesis would also be induced by the up-regulation of pro-angiogenic factors angiopoietin 2 (Ang 2) 7 and vascular endothelial growth factor (VEGF).…”

Identification of immune associated potential molecular targets in proliferative diabetic retinopathy

“…CSF3, COL18A1, CXCR2, CCR1, FGF23, CXCL11, and IL13 were previously reported as related to PDR pathogenesis based on a Laplacian heat diffusion algorithm [20]. Therapeutic strategies targeting MIP1γ to inhibit CCR1-related signaling in retinal endothelial cells might have potential against DR progression [21]. CCR7 significantly enhanced neovascularization and the nonperfusion area in oxygen-induced retinopathy [22].…”

ASK1/p38‑mediated NLRP3 inflammasome signaling pathway contributes to aberrant retinal angiogenesis in diabetic retinopathy

“…2 People's Hospital of Nanjing Medical University (Nanjing, China). Streptozotocin (STZ)-induced hyperglycemic mice were utilized as the type I diabetic-like model associated with retinopathy, as previously described ( 20 ). Male C57/BL/J mice received constitutive intraperitoneal injections of 50 mg/kg STZ in a citric buffer (pH 4.5) once/day for 5 days.…”