Immune Responses in the Glaucomatous Retina: Regulation and Dynamics

Abstract

Glaucoma is a multifactorial disease resulting in progressive vision loss due to retinal ganglion cell (RGC) dysfunction and death. Early events in the pathobiology of the disease include oxidative, metabolic, or mechanical stress that acts upon RGC, causing these to rapidly release danger signals, including extracellular ATP, resulting in micro- and macroglial activation and neuroinflammation. Danger signaling also leads to the formation of inflammasomes in the retina that enable maturation of proinflammatory cytokines such IL-1β and IL-18. Chronic neuroinflammation can have directly damaging effects on RGC, but it also creates a proinflammatory environment and compromises the immune privilege of the retina. In particular, continuous synthesis of proinflammatory mediators such as TNFα, IL-1β, and anaphylatoxins weakens the blood–retina barrier and recruits or activates T-cells. Recent data have demonstrated that adaptive immune responses strongly exacerbate RGC loss in animal models of the disease as T-cells appear to target heat shock proteins displayed on the surface of stressed RGC to cause their apoptotic death. It is possible that dysregulation of these immune responses contributes to the continued loss of RGC in some patients.

Development of Open-Angle Glaucoma in Adults With Seropositive Rheumatoid Arthritis in Korea

“… 52 Furthermore, recent data show that adaptive immune responses strongly exacerbate RGC loss in animal models of glaucoma. 53 …”

Systemic Treatment with Pioglitazone Reverses Vision Loss in Preclinical Glaucoma Models

“…Alternatively, it is possible that pioglitazone mediated protection of RGCs in glaucoma is the result of decreased retinal neuroinflammation. An increasing body of evidence has demonstrated that innate immune responses are not simply a result of elevated IOP, but can actively contribute to RGC dysfunction and loss in glaucoma [ 7 , 54 ]. Activation of PPARγ inhibits the synthesis of pro-inflammatory genes by reducing the transcriptional activity of NFκB, a central regulator of innate immunity [ 55 ].…”

“…The difficulty in developing effective neuroprotective treatments in glaucoma is due, at least in part, to the multifactorial etiology of the disease. Factors including disturbances in ocular blood flow, immune-mediated processes, oxidative stress, metabolic vulnerability, and genetic predisposition have all been implicated in causing the disease [ 4 , 5 , 6 , 7 , 8 , 9 ].…”

“…RGC distress and demise in the glaucomatous retina initiate chronic retinal neuroinflammation that plays an important role in the subsequent pathology of the disease [ 7 , 14 , 15 , 16 ]. Chronic neuroinflammation as a pathogenic mechanism has been observed in several other progressive neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, cerebral ischemia, and traumatic brain injury [ 17 , 18 , 19 ].…”

Spotlight on pyroptosis: role in pathogenesis and therapeutic potential of ocular diseases

“…This reduces the amount of blood flow to the eye, causing hypoxia or ischemia. Furthermore, mechanical damage, oxidative stress, and hypoxia induce mitochondrial dysfunction in RGCs, glial activation, and neuroinflammation, magnifying the pathogenesis of glaucoma [ 156 ]. Chronic neuroinflammation not only directly damages RGCs, but also establishes a pro-inflammatory environment and impairs the immune privilege of the retina [ 156 ].…”