B6-hNLRP3 Mouse

The Cryopyrin protein, encoded by the NOD-like receptor family pyrin domain-containing 3 (NLRP3) gene, is a core component of the inflammasome in the innate immune system. As a member of the NOD-like receptor (NLR) family, NLRP3 is predominantly expressed in leukocytes and chondrocytes. It participates in the host defense against damage and infection by recognizing pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) to activate immune responses ^[1]. In its inactive monomeric state, NLRP3 senses intracellular damage signals, such as abnormal protein aggregates and lipid accumulation. Upon activation, NLRP3 oligomerizes, adopting an active conformation and assembling into inflammasome complexes, subsequently activating Caspase-1 to drive the maturation and secretion of pro-inflammatory cytokines, including IL-1β and IL-18 ^[1-2]. Activated NLRP3 not only induces the release of inflammatory cytokines but also triggers lytic cell pyroptosis. The intracellular components released during pyroptosis can further amplify inflammatory signals, forming a positive feedback loop of autoinflammation. Moreover, IL-1β can exacerbate the inflammatory cascade by stimulating the production of inflammatory markers such as IL-6 and high-sensitivity C-reactive protein (hsCRP) ^[3-4]. Given NLRP3's upstream position relative to IL-1β/IL-18 and other inflammatory factors, targeting its activity can effectively block the self-reinforcing mechanism of chronic inflammation, providing a significant therapeutic strategy for inflammation-related diseases ^[5]. The potential therapeutic areas include Alzheimer’s disease, Parkinson’s disease (via neuroinflammation modulation), inflammatory bowel disease, metabolic dysfunction-associated steatohepatitis (MASH), gout, and obesity-related metabolic inflammation ^[6-7].

The B6-hNLRP3 mouse model was generated by replacing the mouse Nlrp3 genomic region (from the ATG start codon to downstream of the 3'UTR) with the human NLRP3 sequence (from upstream of the ATG start codon to downstream of the 3'UTR), enabling stable expression of human NLRP3 protein. The B6-hNLRP3 mouse is suitable for studying inflammatory mechanisms, autoimmune diseases, neurodegenerative diseases, and metabolic diseases. It also serves as an ideal tool for human NLRP3-targeted drug development and preclinical efficacy evaluation.