Nlrp3 Xenograft-Applicable mouse models

Nlrp3 is the mouse ortholog of human NLRP3 and encodes a pyrin domain, NACHT, leucine rich repeat sensor that assembles the best characterized inflammasome, licensed by deubiquitination through BRCC3, phosphorylation changes at serine and tyrosine residues, and NEK7 binding, then recruited to phosphatidylinositol 4-phosphate rich dispersed trans-Golgi membranes where it nucleates ASC filaments and activates caspase-1 to mature interleukin 1 beta and interleukin 18 and cleave gasdermin D. Activation is indirect, reading potassium efflux, lysosomal damage, and mitochondrial stress rather than a defined ligand, and gain-of-function mutations cause cryopyrin associated periodic syndromes, with knockin alleles such as R258W reproducing human R260W disease. Design accordingly: conditional nulls test requirement, inducible periodic syndrome knockins are essential because constitutive activation is lethal in neonates, and humanization supports MCC950-class inhibitor programs. Because Nlrp1b, Nlrc4, Aim2, and pyrin drive caspase-1 independently, attribute phenotypes with sensor specific alleles rather than Casp1 deletion.

Baseline Nlrp3 loss or humanization may change engraftment. Pilot cohorts de risk larger studies.