Inflammatory resolution and vascular barrier restoration after retinal ischemia reperfusion injury

Abstract

Background Several retinal pathologies exhibit both inflammation and breakdown of the inner blood-retinal barrier (iBRB) resulting in vascular permeability, suggesting that treatments that trigger resolution of inflammation may also promote iBRB restoration. Methods Using the mouse retinal ischemia-reperfusion (IR) injury model, we followed the time course of neurodegeneration, inflammation, and iBRB disruption and repair to examine the relationship between resolution of inflammation and iBRB restoration and to determine if minocycline, a tetracycline derivative shown to reverse microglial activation, can hasten these processes. Results A 90-min ischemic insult followed by reperfusion in the retina induced cell apoptosis and inner retina thinning that progressed for approximately 2 weeks. IR increased vascular permeability within hours, which resolved between 3 and 4 weeks after injury. Increased vascular permeability coincided with alteration and loss of endothelial cell tight junction (TJ) protein content and disorganization of TJ protein complexes. Shunting of blood flow away from leaky vessels and dropout of leaky capillaries were eliminated as possible mechanisms for restoring the iBRB. Repletion of TJ protein contents occurred within 2 days after injury, long before restoration of the iBRB. In contrast, the eventual re-organization of TJ complexes at the cell border coincided with restoration of the barrier. A robust inflammatory response was evident a 1 day after IR and progressed to resolution over the 4-week time course. The inflammatory response included a rapid and transient infiltration of granulocytes and Ly6C+ classical inflammatory monocytes, a slow accumulation of Ly6Cneg monocyte/macrophages, and activation, proliferation, and mobilization of resident microglia. Extravasation of the majority of CD45+ leukocytes occurred from the superficial plexus. The presence of monocyte/macrophages and increased numbers of microglia were sustained until the iBRB was eventually restored. Intervention with minocycline to reverse microglial activation at 1 week after injury promoted early restoration of the iBRB coinciding with decreased expression of mRNAs for the microglial M1 markers TNF-α, IL-1β, and Ptgs2 (Cox-2) and increased expression of secreted serine protease inhibitor Serpina3n mRNA. Conclusions These results suggest that iBRB restoration occurs as TJ complexes are reorganized and that resolution of inflammation and restoration of the iBRB following retinal IR injury are functionally linked.

Retinal degeneration induced in a mouse model of ischemia–reperfusion injury and its management by pemafibrate treatment

“…102 In this regard, many groups have used pharmacological microglial inhibitors to prevent or protect against retinal degeneration in a variety of murine models of retinal degeneration, including retinal I/R injury, optic nerve damage, and NMDA-induced excitotoxicity. 47,53,59,[103][104][105] In our study, we also found microglial activation with increase in Tlrs, Cd68, Iba1, and Il-1β expressions in the ischemic retina, and administration of pemafibrate modulated pathological microglial activation and further prevented retinal dysfunction. However, as microglia have also been thought to have context-dependent roles (either protective or deleterious to neurons), 106,107 we may F I G U R E 3 Molecular changes by oral administrations of pemafibrate in the ischemic retina 1 day after retinal I/R injury.…”

Inhibiting multiple forms of cell death optimizes ganglion cells survival after retinal ischemia reperfusion injury

“…Then, a topical antibiotic and steroid ointment (TobraDex; Alcon Laboratories, Inc., Texas, USA) was applied to the conjunctival sac. Eyes with cannulation-induced cataracts, iris/retinal bleeding, or anterior chamber leakage (leaks can be easily detected as dripping and wetting) were excluded [ 39 , 40 ].…”

Nicotinamide Mononucleotide Prevents Retinal Dysfunction in a Mouse Model of Retinal Ischemia/Reperfusion Injury

“…Previous reports from us and others have suggested that reductions in pathologic retinal inflammatory cells could be beneficial for retinal neuronal protection in a murine model of retinal I/R injury [ 13 , 32 , 33 ]. The therapeutic strategy of modulating pathologic inflammatory cells for neuroprotection can be seen in brain injury, rather than just retinal I/R injury [ 34 , 35 , 36 ].…”