IL-1 Family Members Mediate Cell Death, Inflammation and Angiogenesis in Retinal Degenerative Diseases

Abstract

Inflammation underpins and contributes to the pathogenesis of many retinal degenerative diseases. The recruitment and activation of both resident microglia and recruited macrophages, as well as the production of cytokines, are key contributing factors for progressive cell death in these diseases. In particular, the interleukin 1 (IL-1) family consisting of both pro- and anti-inflammatory cytokines has been shown to be pivotal in the mediation of innate immunity and contribute directly to a number of retinal degenerations, including Age-Related Macular Degeneration (AMD), diabetic retinopathy, retinitis pigmentosa, glaucoma, and retinopathy of prematurity (ROP). In this review, we will discuss the role of IL-1 family members and inflammasome signaling in retinal degenerative diseases, piecing together their contribution to retinal disease pathology, and identifying areas of research expansion required to further elucidate their function in the retina.

Keywords: IL-1 (interleukin-1); IL-1b; age-related macular degeneration (AMD); cytokine; inflammasome; inflammation; photoreceptor cell death; retinal degeneration.

Figure 1

Proposed roles of IL-1 family members on cell death, inflammation, and angiogenesis in the degenerating retina. IL-1β production by activated microglia and macrophages may lead to increased chemokine and cytokine release from Müller and RPE cells, promoting further macrophage recruitment to the damaged site and ultimately resulting in photoreceptor and RPE cell death (16, 18, 108, 109). This may occur through IL-1R expression on Müller and RPE cells (18), through which IL-1α may also exert its inflammatory functions (96, 97). IL-1Ra, a competitive antagonist for IL-1R, is dysregulated in retinal degenerations (27, 44). IL-33, a less-characterized IL-1 ligand in the retina, may play a role in cytokine regulation, specifically in dry AMD pathogenesis (45, 128). IL-18, IL-37 and IL-38 all have reported roles in regulating neovascularisation; however, have been shown to have both pro- or anti- angiogenic effects, with IL-18 dysregulation conferring protection against neovascularisation in wet AMD (31), but detrimental effects in dry AMD (35), DR (141), and potentially ROP (188). Although not widely characterized, IL-37 may play a pro-angiogenic role in DR (47) while IL-38 is suggested to have anti-angiogenic roles in ROP (48).