All Phenotypes Brcc3<em1Bcgen> MGI Mouse

mortality/aging ( J:277205 )

N	• mice are viable and exhibit normal development and life spans

abnormal macrophage physiology ( J:277205 )

• in vitro, LPS-primed bone marrow-derived macrophages (BMDMs) show impaired pro-caspase-1 and pro-IL-1beta processing in response to ATP, nigericin, and MSU stimulation, consistent with defective activation of the NLRP3 inflammasome

• LPS-primed BMDMs show a significant reduction in PYCARD/ASC speck formation in response to nigericin stimulation

• LPS-primed BMDMs show no deubiquitination of NLRP3 in response to stimulation with nigericin, unlike similarly treated wild-type BMDMs; notably, the poly-ubiquitination level of the endogenous NLRP3 protein is normal after LPS priming

• however, LPS-primed BMDMs show normal pro-caspase-1 and pro-IL-1beta processing in response to flagellin and poly(dA:dT) treatment, and normal PYCARD/ASC speck formation after poly(dA:dT) transfection

decreased circulating interleukin-1 beta level ( J:277205 )

• in an LPS-induced sepsis model, mice i.p. injected with LPS (15 mg/kg) show a significant reduction in serum IL-1beta levels at 3 h post-injection

abnormal interleukin-1 beta secretion ( J:363478 )

• BMDMs infected with lentivirus overexpressing WWP2 (WW domain containing E3 ubiquitin protein ligase 2; an E3 ubiquitin ligase of BRCC3) and stimulated with LPS + nigericin fail to show a decrease in IL-1beta release, unlike similarly treated wild-type BMDMs, suggesting that WWP2 regulates NLRP3 inflammasome activation in a BRCC3-dependent manner

decreased interleukin-1 beta secretion ( J:277205 )

• LPS-primed BMDMs secrete significantly less mature IL-1beta in response to NLRP3 inflammasome stimuli, including ATP, nigericin, monosodium urate crystals (MSU), and aluminum (Alum), indicating defective activation of the NLRP3 inflammasome

• in vivo, mice i.p injected with MSU show a significant decrease in IL-1beta secretion in the peritoneal lavage fluid, whereas inflammasome-independent TNF-alpha secretion is normal

• however, LPS-primed BMDMs show normal IL-1beta secretion in response to Salmonella flagellin and poly(dA:dT), indicating normal activation of the respective NLRC4 and AIM2 inflammasomes

decreased inflammatory response ( J:277205 )

• in a NLRP3-dependent peritonitis model, mice i.p. injected with MSU show a significantly lower IL-1beta secretion in the lavage fluid and impaired recruitment of neutrophils and inflammatory monocytes to the peritoneal cavity relative to wild-type controls

decreased susceptibility to endotoxin shock ( J:277205 )

• in an LPS-induced sepsis model, mice i.p. injected with LPS (15 mg/kg) show significantly lower serum IL-1beta levels and markedly increased survival, with ~90% surviving to 9 days whereas less than 25% of wild-type controls survive to 4-9 days after LPS injection