Figure 1. The inflammasome in age-related macular degeneration. Two groups have independently found that the inflammasome and IL-18 play a key role in the development and progression of age-related macular degeneration (AMD).

The inflammasome is a cytosolic, multiprotein complex that triggers the innate immune response to microbial toxins as well as to endogenous proteins, lipids and oligonucleotides.

In a paper published in Nature Medicine, Doyle et al. showed that protein aggregates in the macula known as drusen activated the inflammasome in monocytes [a(1) and b(1)] to trigger the local production of proinflammatory cytokine IL-18 [c(1)]. The result was downregulation of proangiogenic VEGF and reduced eye damage [d(1) and e(1)] in a mouse model of wet AMD.

In a paper published in Cell, Tarallo et al.
showed that Alu RNA in the macula plus reactive oxygen species (ROS) activated the inflammasome in retinal pigment epithelial (RPE) cells [a(2) and b(2)] to trigger production of IL-18 [c(2)]. The result was activation of myeloid differentiation primary response gene 88 (MYD88), increased RPE degeneration and eye damage [d(2) and e(2)] in a mouse model of geographic atrophy, an advanced form of dry AMD.

Doyle et al. are now developing adeno-associate virus (AAV) vector-mediated delivery of pro-IL-18 gene therapy to enhance IL-18
activity in the eye and treat wet AMD, whereas Tarallo et al. are developing MYD88 inhibitors to block IL-18 activity and treat dry AMD.