Volume 30, Issue 6, Pages (June 2009)

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Volume 30, Issue 6, Pages 875-887 (June 2009) Inflammasome-Mediated Disease Animal Models Reveal Roles for Innate but Not Adaptive Immunity  Susannah D. Brydges, James L. Mueller, Matthew D. McGeough, Carla A. Pena, Amirhossein Misaghi, Chhavi Gandhi, Chris D. Putnam, David L. Boyle, Gary S. Firestein, Anthony A. Horner, Pejman Soroosh, Wendy T. Watford, John J. O'Shea, Daniel L. Kastner, Hal M. Hoffman  Immunity  Volume 30, Issue 6, Pages 875-887 (June 2009) DOI: 10.1016/j.immuni.2009.05.005 Copyright © 2009 Elsevier Inc. Terms and Conditions

Figure 1 CAPS Mutations Cause Severe Inflammatory Disease Lethal in the Perinatal Period (A) Survival (top) and growth (bottom) curves for WT (n = 86, WT CreZ shown only), Nlrp3A350V/+CreZ (n = 50), and Nlrp3A350V/+CreL (n = 40) mice. A log-rank (Mantel-Cox) test comparing Nlrp3A350V/+CreZ and Nlrp3A350V/+CreL survival curves yielded a p value < 0.0001. Error bars shown for mean daily weights on growth curves are SD (n = 1–17). (B) Nlrp3A350V/+CreL, day 8, tissue sections from synovium, liver, meninges, and conjunctiva, stained with hematoxylin and eosin at 10× and 40× (insets) magnification. (C) Birth table of pups resulting from CreL+/+ × Nlrp3A350VNeoR/+ or Nlrp3L351PNeoR/+ matings, with 50% of offspring expected to be mutant. Shown: total pups; total mutant pups days 1 and 2 after birth. Immunity 2009 30, 875-887DOI: (10.1016/j.immuni.2009.05.005) Copyright © 2009 Elsevier Inc. Terms and Conditions

Figure 2 Multiple Cytokines Are Upregulated in the Serum and Skin of Nlrp3A350V/+CreL Mice (A) Luminex analysis of serum obtained at days 6–8 from WT and Nlrp3A350V/+CreL pups, n = 10–12 mice, each graph point represents one mouse, mean and SEM are shown. (B) Immunohistochemistry on skin from WT and Nlrp3A350V/+CreL pups for IL-1β or IL-6 (red stain), and an isotype control followed by hematoxylin staining. Similar staining was observed on sections from Nlrp3A350V/+CreZ mice (not shown). Immunity 2009 30, 875-887DOI: (10.1016/j.immuni.2009.05.005) Copyright © 2009 Elsevier Inc. Terms and Conditions

Figure 3 Myeloid Cells from Nlrp3A350V/+CreT and Nlrp3L351P/+CreT Mice and CAPS Patients React Similarly to Innate Stimuli (A and B) Tamoxifen-treated Nlrp3A350V/+CreT, Nlrp3L351P/+CreT, and littermate WT BMDC were incubated with varying amounts of (A) crude LPS or (B) pure LPS (100 ng/ml) with and without ATP (5 mM). (C) Tamoxifen-treated peritoneal macrophages (PM) were incubated with pure LPS with and without ATP. (A–C) n = 2–3 mice with 3 wells each/genotype. Bar graphs show mean + SD. (D) Immunoblotting for IL-1β or actin loading control, Nlrp3A350V/+CreT BMDC lysates (left), and supernatants (right). (E) In vitro stimulation of monocytes from three CAPS patients and three normal human controls with pure LPS with and without ATP. (F) In vitro cold stimulation of WT, Nlrp3A350V/+CreT, and Nlrp3L351P/+CreT BMDC, n = 2–3. Cells were incubated at 32°C overnight. (G) In vitro cold stimulation of monocytes from five FCAS patients and two normal human controls, 4 hr and overnight. Also shown, incubation at 37°C. (A–C, E–G) IL-1β in the supernatants was measured by ELISA. Immunity 2009 30, 875-887DOI: (10.1016/j.immuni.2009.05.005) Copyright © 2009 Elsevier Inc. Terms and Conditions

Figure 4 IL-1β Is Required for Murine Disease (A) Nlrp3A350V/+CreL and wild-type littermates were treated with subcutaneously injected mIL-1 Trap every other day beginning day 1–2 after birth. Survival (left) (n = 9) and growth (right) (n = 2–9 mice), p = 0.003 by log-rank (Mantel-Cox) comparison. (B) Survival (left) and growth (right) of Nlrp3A350V/+CreL Il1r1+/− and Nlrp3A350V/+CreL Il1r1−/− mice (n = 13–18 for survival and 1–9 for growth). (C) Survival (left) and growth (right) of Nlrp3L351P/+CreL Il1r1−/− mice (n = 33 for survival and 2–12 for growth). Error bars shown for mean daily weights on growth curves are SD. (D) Luminex analysis of serum from Nlrp3A350V/+CreL Il1r1−/− mice, n = 5, compared with Luminex data from WT and Nlrp3A350V/+CreL mice in Figure 2 (averages and SEM shown only). Immunity 2009 30, 875-887DOI: (10.1016/j.immuni.2009.05.005) Copyright © 2009 Elsevier Inc. Terms and Conditions

Figure 5 Nlrp3A350V/+CreT BMDC Drive an Inflammatory T Cell Phenotype (A) Tamoxifen-treated BMDC from Nlrp3A350V/+CreT and WT mice were treated with LPS and stained for CD40, OX40L, and MHC class II receptor. (B–I) BMDC were plated with OT II naive T cells and OVA antigen under Th1 (B, E), Th2 (C, F), or Th17 (H) cell polarizing conditions or left unpolarized (D, G, I). (B–D) Flow cytometry analysis of intracellular IFN-γ and IL-17. (E–I) Luminex analysis of culture supernatants for IFN-γ, IL-17, IL-5, and IL-4. Immunity 2009 30, 875-887DOI: (10.1016/j.immuni.2009.05.005) Copyright © 2009 Elsevier Inc. Terms and Conditions

Figure 6 An Intact Inflammasome Is Required for Pathology Mediated by NLRP3 Knockin Mutations, but T and B Cells Are Not Nlrp3A350VneoR/+ mice were bred with Pycard−/−, Rag1−/−, and Nlrp3−/− mice. (A) Survival (top) and growth (bottom) of Nlrp3A350V/+CreL Rag1−/− (n = 1–3 for growth, 6 for survival), Nlrp3A350V/+CreL Pycard−/− (n = 1–3 for growth, 7 for survival), and Nlrp3A350V/−CreL (n = 1–3 for growth, 7 for survival) mice. (B) Survival (top) and growth (bottom) of Nlrp3L351P/+CreL Pycard−/− mice (n = 13 for survival, 2–3 for growth). Error bars shown for mean daily weights on growth curves are SD. Immunity 2009 30, 875-887DOI: (10.1016/j.immuni.2009.05.005) Copyright © 2009 Elsevier Inc. Terms and Conditions