Time-dependent LXR/RXR pathway modulation characterizes capillary remodeling in inflammatory corneal neovascularization

Abstract

Inflammation in the normally immune-privileged cornea can initiate a pathologic angiogenic response causing vision-threatening corneal neovascularization. Inflammatory pathways, however, are numerous, complex and are activated in a time-dependent manner. Effective resolution of inflammation and associated angiogenesis in the cornea requires knowledge of these pathways and their time dependence, which has, to date, remained largely unexplored. Here, using a model of endogenous resolution of inflammation-induced corneal angiogenesis, we investigate the time dependence of inflammatory genes in effecting capillary regression and the return of corneal transparency. Endogenous capillary regression was characterized by a progressive thinning and remodeling of angiogenic capillaries and inflammatory cell retreat in vivo in the rat cornea. By whole-genome longitudinal microarray analysis, early suppression of VEGF ligand-receptor signaling and inflammatory pathways preceded an unexpected later-phase preferential activation of LXR/RXR, PPARα/RXRα and STAT3 canonical pathways, with a concurrent attenuation of LPS/IL-1 inhibition of RXR function and Wnt/β-catenin signaling pathways. Potent downstream inflammatory cytokines such as Cxcl5, IL-1β, IL-6 and Ccl2 were concomitantly downregulated during the remodeling phase. Upstream regulators of the inflammatory pathways included Socs3, Sparc and ApoE. A complex and coordinated time-dependent interplay between pro- and anti-inflammatory signaling pathways highlights a potential anti-inflammatory role of LXR/RXR, PPARα/RXRα and STAT3 signaling pathways in resolving inflammatory corneal angiogenesis.Electronic supplementary materialThe online version of this article (10.1007/s10456-018-9604-y) contains supplementary material, which is available to authorized users.

Repeat Corneal Neovascularization is Characterized by More Aggressive Inflammation and Vessel Invasion Than in the Initial Phase

“…1). 16,[20][21][22][23][24][25][26] For experiments involving treatment, dexamethasone (1 mg/mL Opnol; Clean Chemical Sweden AB, Borlange, Sweden) was given topically to the re-sutured eye immediately after suture placement and after that three times daily for 3 days. The control group was not treated.…”

“…Experimental design followed to investigate repeat neovascularization in the cornea using the suture model of inflammatory-induced corneal neovascularization. 16,[20][21][22][23][24][25][26] furthest invading vessel tips in slit-lamp photographs of the cornea and by the limbal border.…”

“…Notably, the 'leukocyte extravasation' pathway activation increased, while the dual pathways 'LPS/IL-1-mediated inhibition of RXR function' and 'LXR/RXR activation' had a stronger proinflammatory profile. 25 Specific to the repeat phase, both innate and adaptive immune pathways were activated, as well as the production of nitric oxide (NO) and reactive oxygen species (ROS) pathway. The upstream regulatory analysis revealed that in initial neovascularization, Il1b was the most active upstream regulator with activation score 3.8, and with a P value of overlap (between the DEG and QIAGEN knowledge base) of 7.5EÀ04 (Fig.…”

Inhibitors of corneal inflammation and angiogenesis : Prospectives and challenges

“…In Paper IV, endogenous inhibition of inflammation was studied during the physiologic wound healing response. The endogenous healing process is comparable to the stabilization phase obtained by removing the angiogenic stimulus, studied by our group in another doctoral thesis: the hypothesis being that an endogenous inflammatory as well as angiogenic switch could be activated and deactivated through specific pathways, and that coordinated delivery of anti-VEGF and anti-inflammatory therapy could transform active sprouts into mature, non-leaky and non-damaging functional capillaries 113,325 .…”

A metabolomics-binding network pharmacology study of Zuojin Pill intervention in chronic atrophic gastritis induced by Helicobacter pylori

“…The results showed that 124 chemical components originating from ZJP acted directly with 12 potential protein targets, suggesting the advantages of multiple components in ZJP in regulating endogenous metabolic changes in the body, showing the advantages of ZJP in the clinical treatment of CAG. Twelve targets were strongly associated with in ammation, including MAPK1, PTGS2, PTGS1, RXRA, ADRA1B, RB1, ADRB1, E2F1, SCN5A, PKIAIGF2, and GABRA1 [34][35][36][37]. Therefore, to verify the accuracy of the network pharmacology predictions and to further elucidate the potential mechanism of ZJP, we further tested the expression of these genes in gastric tissues of CAG rats.…”