Findings from a study published in Cell Death & Disease evaluated the role of nucleotide-binding oligomerization (NOD)-like receptor protein 3 (NLRP3) and its downstream effector caspase 1 (Casp1) in mediating early age-related macular degeneration (AMD)-like pathology.
That sounds … intense. Let’s begin by digging into some biochemistry.
Chronic, unresolved inflammation has long been speculated to serve as an initiating and propagating factor in numerous neurodegenerative diseases, including AMD.
How: Intracellular multiprotein complexes called inflammasomes in combination with activated caspases facilitate the production of pro-inflammatory cytokines—such as interleukin 1-beta (IL-1 beta) and 18 (IL-18)—which can serve as recruitment signals for immune cells and initiate clearance of viruses, pathogens, or microbes.
- As such: Activation of the NLRP3 inflammasome is critical for remediation of acute viral or microbial infections.
I’m sensing a but …
However: If persistently activated, sustained NLRP3 activity can cause chronic and unresolved inflammation, leading to tissue damage and degeneration of sensitive cell lineages—including neurons.
Consequently: Reducing chronic NLRP3 inflammasome activation has been a target for minimizing age-related neurodegeneration pathology in both the eye and brain.
Now bring this back to AMD.
Previous studies have implicated NLRP3 (or its downstream products) in the progression of varying stages of AMD:
- Geographic atrophy (GA): Detrimental role of the NLRP3 inflammasome in the onset of GA
- Wet AMD: Cytokines like IL-18 appear to be protective against neovascularization
Plus: More recently, a series of studies found a harmful role of NLRP3 in non-AMD degenerative retinal diseases, such as diabetic retinopathy.
Alrighty, now to the study in question.
The research team tested the role of NLRP and its downstream effector 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.
How: Via the generation and ocular characterization of R345W+/+ knockin mice lacking either NLRP3 or Casp1.
Break that down for me.
The study authors explained that AMD is an etiologically complex and primate-specific, age-related disease, making it difficult to study and confirm the molecular basis of AMD within a laboratory and on a reasonable timeframe.
As such: The research team focused on a monogenic, autosomal dominant, early-onset form of AMD called ML/DHRD, which is caused by a p.R345W mutation in the extracellular matrix (ECM) protein epidermal growth factor-containing fibulin-like ECM protein 1 (EFEMP1).
- Note: +/+ refers to the fact that R345W+/+ mice harbored two copies of the p.R345W EFEMP1 mutation.
And the findings?
Compared to age-matched controls, R345W+/+ knockin mice demonstrated increases in the following:
- Müller cell gliosis
- Subretinal ionized calcium-binding adapter molecule 1 (Iba-1) cells
- Higher NLRP3 immunoreactivity in the retina
- Transcriptional upregulation in the retinal pigment epithelium (RPE)/choroid of:
- Complement component 3 (C3)
- NLRP3
- Pro-IL-1 beta
- Pro-caspase-1
- Tissue inhibitor of matrix metalloproteinase 3 (MMP-3)
In addition: The research team reported an age-related increase in BLamD formation in the R345W+/+ mice.
Anything else?
Genetic elimination of either NLRP3 or Casp1 significantly reduced both the size and coverage of BLamDs in the R345W+/+ background.
- Meaning: NLRP3 may be an important and underappreciated pathway that could affect ML/DHRD onset and progression.
Further: NLRP3 knockout reduced spontaneous, age-related BLamDs in WT mice, suggesting translatability of these findings not only to rare inherited retinal dystrophies, but potentially AMD as well.
Expert opinion?
Of note: Genetic elimination of C3 prevented BLamD formation in R345W mice, while removal of C5 had no effect.
“Based on these findings, it is interesting to speculate that perhaps FDA-approved C3 inhibitors for GA such as Pegcetacoplan (SYFOVRE) may ultimately be repurposed for use in ML/DHRD, possibly with better functional outcomes than has occurred in dry AMD,” the study authors explained.
Take home.
These findings highlight the importance of NLRP3 in BLamD formation and joins a growing body of literature identifying potential therapeutic approaches to alleviating or delaying pathology in ML/DHRD.
Moreover: The results support the idea that certain retinal dystrophies with phenotypic similarities to AMD could be used as proving grounds to develop breakthroughs in etiologically complex, yet prevalent diseases such as AMD.