Immunological Landscape of Retinal Ischemia-Reperfusion Injury: Insights into Resident and Peripheral Immune Cell Responses

Abstract

Retinal ischemia-reperfusion injury (RIRI) is a complex condition characterized by immune cellmediated inflammation and consequent neuronal damage. This review delves into the immune response mechanisms in RIRI, particularly emphasizing the roles played by resident and peripheral immune cells. It highlights the pivotal role of microglia, the primary resident immune cells, in exacerbating neuroinflammation and neuronal damage through their activation and subsequent release of pro-inflammatory mediators. Additionally, the review explores the contributions of other glial cell types, such as astrocytes and Müller cells, in modulating the immune response within the retinal environment. The dual role of the complement system in RIRI is also examined, revealing its complex functions in both safeguarding and impairing retinal health. Inflammasomes, triggered by various danger signals, are discussed as crucial contributors to the inflammatory pathways in RIRI, with an emphasis on the involvement of different NOD-like receptor family proteins. The review further analyzes the infiltration and impact of peripheral immune cells like neutrophils, macrophages, and T cells, which migrate to the retina following ischemic injury. Critical to this discussion is the interplay between resident and peripheral immune cells and its implications for RIRI pathophysiology. Finally, the review outlines future research directions, focusing on basic research and the potential for clinical translation to enhance understanding and treatment of RIRI.

Role of inflammation in a rat model of radiation retinopathy

“…Specific markers were used to establish that they were activated into macrophages. Indeed, these inflammatory cells can undergo phenotypic and functional modifications to become macrophages, which are able to release inflammatory cytokines to recruit inflammatory effector cells and thus exacerbate inflammation [ 50 ]. Moreover, there are several types of macrophages, depending on their anti-inflammatory (M2), pro-inflammatory (M1), or perivascular characteristics [ 47 , 50 , 51 ].…”

“…Indeed, these inflammatory cells can undergo phenotypic and functional modifications to become macrophages, which are able to release inflammatory cytokines to recruit inflammatory effector cells and thus exacerbate inflammation [ 50 ]. Moreover, there are several types of macrophages, depending on their anti-inflammatory (M2), pro-inflammatory (M1), or perivascular characteristics [ 47 , 50 , 51 ]. The latter, also called vessel-associated microglia, are involved in vessel maintenance and repair as well as in the clearance of infiltrating cells of the neuro-glial-vascular unit [ 52 ], which could be relevant in our RR where vessels are altered.…”

“…Microglial morphology is important since it indicates the inflammatory status of microglia. The moderate but thick ramifications indicate that they are reactive, while the round or amoeboid shape indicates that they are phagocytic, suggesting a macrophage phenotype [ 50 , 63 ]. This finding is consistent with our observations: after irradiation, the microglial cells migrate toward the RPE, differentiate into macrophages upon arrival at the RPE, where they can phagocytose cellular debris from dead photoreceptors, RPE or other cells.…”