Species-specific NLRP3 regulation and its role in CNS autoinflammatory diseases
Beverly H. Koller,
MyTrang Nguyen,
John N. Snouwaert,
Christopher A. Gabel,
Jenny P.-Y. Ting
Affiliations
Beverly H. Koller
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Corresponding author
MyTrang Nguyen
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
John N. Snouwaert
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Christopher A. Gabel
NodThera, 454 North 34th Street, Seattle, WA 98103, USA
Jenny P.-Y. Ting
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Center for Translational Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Corresponding author
Summary: The NLRP3 inflammasome is essential for caspase-1 activation and the release of interleukin (IL)-1β, 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.
