Genetic removal of Nlrp3 protects against sporadic and R345W Efemp1-induced basal laminar deposit formation

Ortega, A. J.; Daniel, S.; Renwick, M.; Kambhampati, P.; Thompson, K. N.; Collier, G. E.; Baker, E. L.; Zaki, H.; Hulleman, J. D.

doi:10.1101/2024.10.14.618289

bioRxiv · 10.1101/2024.10.14.618289

Genetic removal of Nlrp3 protects against sporadic and R345W Efemp1-induced basal laminar deposit formation

Ortega, A. J.·Daniel, S.·Renwick, M.·Kambhampati, P.·Thompson, K. N.·Collier, G. E.·Baker, E. L.·Zaki, H.·Hulleman, J. D.

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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+ microglial 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, idiopathic BLamDs in WT mice, suggesting translatability of our findings not only to rare inherited retinal dystrophies, but also potentially to AMD itself.

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Ortega, A. J., Daniel, S., Renwick, M., Kambhampati, P., Thompson, K. N., Collier, G. E., Baker, E. L., Zaki, H., Hulleman, J. D.. 2024-10-17. Genetic removal of Nlrp3 protects against sporadic and R345W Efemp1-induced basal laminar deposit formation. https://doi.org/10.1101/2024.10.14.618289

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