Inflammatory Resolution and Vascular Barrier Restoration after Retinal Ischemia Reperfusion Injury [post]

Steven F Abcouwer, Sumathi Shanmugam, Arivalagan Muthusamy, Cheng-mao Lin, Dejuan Kong, Heather Hager, Xuwen Liu, David A. Antonetti
2021 unpublished
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. 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
more » ... rmine if minocycline, a tetracycline derivative shown to reverse microglial activation, can hasten these processes. 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 lasted for at least 2 weeks and 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. Whereas repletion of TJ protein content occurred within days, restoration of the iBRB coincided with eventual re-organization of TJ complexes at the cell border. 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 Ly6C neg monocyte/macrophages, and activation, proliferation and mobilization of resident microglia. 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 promoted early restoration of the iBRB. These results suggest that resolution of inflammation and restoration of the iBRB following retinal IR injury are functionally linked.
doi:10.21203/rs.3.rs-314870/v1 fatcat:uh2g7yrmhjgk7a4ucccjnlkl4u