Species-specific NLRP3 regulation and its role in CNS autoinflammatory diseases.
Cell Rep
; 43(3): 113852, 2024 Mar 26.
Article
in En
| MEDLINE
| ID: mdl-38427558
ABSTRACT
The NLRP3 inflammasome is essential for caspase-1 activation and the release of interleukin (IL)-1ß, IL-18, and gasdermin-D in myeloid cells. However, research on species-specific NLRP3's physiological impact is limited. We engineer mice with the human NLRP3 gene, driven by either the human or mouse promoter, via syntenic replacement at the mouse Nlrp3 locus. Both promoters facilitate hNLRP3 expression in myeloid cells, but the mouse promoter responds more robustly to LPS. Investigating the disease impact of differential NLRP3 regulation, we introduce the D305N gain-of-function mutation into both humanized lines. Chronic inflammation is evident with both promoters; however, CNS outcomes vary significantly. Despite poor response to LPS, the human promoter results in D305N-associated aseptic meningitis, mirroring human pathology. The mouse promoter, although leading to increased CNS expression post-LPS, does not induce meningitis in D305N mutants. Therefore, human-like NLRP3 expression may be crucial for accurate modeling of its role in disease pathogenesis.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Hereditary Autoinflammatory Diseases
/
NLR Family, Pyrin Domain-Containing 3 Protein
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell Rep
Year:
2024
Document type:
Article