Cellular Stress Response and Immune Signaling in Retinal Ischemia-Reperfusion Injury

Abstract

Ischemia-reperfusion injury is a well-known pathological hallmark associated with diabetic retinopathy, glaucoma, and other related retinopathies that ultimately can lead to visual impairment and vision loss. Retinal ischemia pathogenesis involves a cascade of detrimental events that include energy failure, excitotoxic damage, calcium imbalance, oxidative stress, and eventually cell death. Retina for a long time has been known to be an immune privileged site; however, recent investigations reveal that retina, as well as the central nervous system, elicits immunological responses during various stress cues. Stress condition, such as reperfusion of blood supply post-ischemia results in the sequestration of different immune cells, inflammatory mediators including cytokines, chemokines, etc., to the ischemic region, which in turn facilitates induction of inflammatory conditions in these tissues. The immunological activation during injury or stress per se is beneficial for repair and maintenance of cellular homeostasis, but whether the associated inflammation is good or bad, during ischemia-reperfusion injury, hitherto remains to be explored. Keeping all these notions in mind, the current review tries to address the immune response and host stress response mechanisms involved in ischemia-reperfusion injury with the focus on the retina.

Keywords: immune response; inflammation; ischemia–reperfusion; retina; stress response.

Figure 1

Multi-faceted cellular responses during retinal ischemia–reperfusion injury. Different aspects of immune signaling and host responses associated with ischemia–reperfusion injury in retina.

Figure 2

Toll-like receptor signaling during ischemia–reperfusion injury. Specific receptors, such as TLRs, are activated during ischemia–reperfusion through damage-associated molecular patterns (DAMPs), which activate downstream MAPK pathway and via different transcription factors such as NFκB and c-fos-c-jun, and translate different cell adhesion and inflammatory molecules, which causes inflammation. This pathway also acts through inflammasomes formation and through caspase 1 activation, which also results in inflammation.

Figure 3

Trafficking of T cells after ischemia–reperfusion and related downstream response. Different T cell populations involved in ischemia–reperfusion injury pathogenesis. These T cells infiltrate upon breach of blood-retina barrier due to ischemia injury and different populations stimulate varied downstream signaling through cytokine/chemokine mediators (broken lines denotes the paradox outcomes).