Figure 7. 15d-PGJ2 inhibition of the inflammasome in mice.

(A, B) A well-established mouse monosodium urate induced peritonitis model was utilized to assess impact of 15d-PGJ2 on the NLRP3 inflammasome in vivo. C57BL/6J mice (n=9/group) were injected IP with 125 μg of 15d-PGJ2 or vehicle (10% DMSO in PBS) at 5 min prior and 4 h after administration of monosodium urate (MSU) crystals. Control mice were injected with vehicle (n=4) or drug (n=7) alone. MSU crystals were injected into mice (4 mg/250 ul PBS, IP) and after 6 h infiltrating cells were counted (A) and IL-1β levels assessed (B). P-values (unpaired t-test) comparing the MSU (+vehicle) groups to MSU (+15d-PGJ2) groups are <0.0001 in both panels. (C, D) Anthrax spore-resistant NLRP1b^S/S-expressing Balb/cJ (n=5) and C57BL/6NTacNlrp1b^S/S (n=5) mice were treated with 15d-PGJ2 (100 μg, 200 μl, SC, at 5 min and 1 h post spore infection) or with vehicle and infected with 2×10⁷ A35 spores (C) or 4×10⁷ A35 spores (D). Spore-sensitive NLRP1b^R/R-expresssing C57BL/6J (n=5) and C57BL/6NTacNlrp1b^R;R (n=4) mice infected with the same spore dose served as controls. For panel C, the P-value comparing vehicle-treated, spore-infected Balb/cJ mice to the 15d-PGJ2-treated infected Balb/cJ group or infected C57BL/6J mice is <0.007. There is no significant difference between the infection susceptibility for drug-treated Balb/cJ mice and genetically susceptible C57BL/6J mice infected with B. anthracis spores. For panel D, the P-value comparing vehicle-treated, spore-infected C57BL/6NTacNlrp1b^S/S to 15d-PGJ2-treated infected group is 0.0065. The P-value comparing vehicle-treated, spore-infected C57BL/6NTacNlrp1b^S/S to similarly infected C57BL/6NTacNlrp1b^R;R is 0.00429. The susceptibility curve for the drug-treated and spore-infected C57BL/6NTacNlrp1b^S/S mice is not significantly different from the spore-infected genetically susceptible C57BL/6NTacNlrp1b^R/R mice. The Log-rank test was used for assessment of all P-values in panels C and D.