# Genetic removal of Nlrp3 protects against age-related and R345W Efemp1-induced basal laminar deposit formation

## TL;DR

Removing the Nlrp3 gene protects mice from age-related and mutation-induced eye damage linked to macular degeneration.

## Contribution

This study shows that Nlrp3 and Casp1 are key drivers of early AMD-like pathology in mice.

## Key findings

- Nlrp3 or Casp1 removal reduced basal laminar deposits in R345W+/+ mice.
- Nlrp3 knockout also reduced age-related deposits in wild-type mice.
- Nlrp3 is linked to inflammation and AMD-like pathology in mouse models.

## Abstract

Chronic, unresolved inflammation has long been speculated to serve as an initiating and propagating factor in numerous neurodegenerative diseases, including a leading cause of irreversible blindness in the elderly, age-related macular degeneration (AMD). Intracellular multiprotein complexes called inflammasomes in combination with activated caspases facilitate production of pro-inflammatory cytokines such as interleukin 1 beta. Specifically, the nucleotide-binding oligomerization (NOD)-like receptor protein 3 (NLRP3) has received heightened attention due to the wide range of stimuli to which it can respond and its potential involvement in AMD. In this study, we directly tested the role of Nlrp3 and its downstream effector, caspase 1 (Casp1) in mediating early AMD-like pathology (i.e., basal laminar deposits [BLamDs]) in wild-type (WT) mice and the Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD) mouse model (p.R345W mutation in Efemp1). Compared to aged-matched controls, R345W+/+ knockin mice demonstrated increased Muller cell gliosis, subretinal Iba-1+ cells, higher Nlrp3 immunoreactivity in the retina, as well as significant transcriptional upregulation of complement component 3, Nlrp3, pro-Il1b, pro-caspase-1, and tissue inhibitor of matrix metalloproteinase 3 in the retinal pigmented epithelium (RPE)/choroid. These findings were accompanied by an age-related increase in BLamD formation in the R345W+/+ mice. Genetic elimination of either Nlrp3 or Casp1 significantly reduced both the size and coverage of BLamDs in the R345W+/+ background, highlighting an important and underappreciated pathway that could affect ML/DHRD onset and progression. Moreover, Nlrp3 knockout reduced spontaneous, age-related BLamDs in WT mice, suggesting translatability of our findings not only to rare inherited retinal dystrophies, but also potentially to AMD itself.