Elevated ATP, cytokines and potential microglial inflammation distinguish exfoliation glaucoma from exfoliation syndrome

Abstract

Glaucoma is the second leading cause of blindness. Exfoliation syndrome (XFN) is a risk factor for exfoliation glaucoma (XFG) which is a secondary open angle glaucoma. XFG is difficult to manage with a worse prognosis. Though 40% of the XFN progress to XFG, there are no predictive markers to identify the susceptible patients. Herein, we analyze clinical data, ATP levels in aqueous humor and cytokines in plasma to identify alteration that help distinguish XFN from XFG. Our results show characteristic clinical features of XFG compared to XFN and controls. Elevated levels of ATP in aqueous humor were observed in XFG compared to XFN and cataract controls while elevated levels of plasma cytokines were observed in XFG compared to XFN, cataract controls and healthy controls. Microglia are immune cells in the retina implicated in glaucoma. TNFα plays a predominant role in microglial inflammation and is implicated in neurodegeneration. Using in vitro N9 microglial cell culture model, we demonstrate that TNFα modulated expression of cytokines and chemotaxis is dependent on P2 receptors like P2X₇, P2Y₁₂ and P2Y₆. In addition, ATP also induce expression of TNFα which might act as a feed forward loop. The TNFα induced inflammation is dependent on downstream signaling modules like PI3K, JNK and ROS. Taken together, our results show that elevated ATP in aqueous humor, plasma cytokines and inflammation potentially involving microglia distinguish XFG from XFN. Purinergic receptors might be potential therapeutic targets in XFG.

Keywords: Chemotaxis; Glaucoma; Inflammation; Microglial inflammation; Purinergic signaling.