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Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies
Susannah D. Brydges, … , James L. Mueller, Hal M. Hoffman
Susannah D. Brydges, … , James L. Mueller, Hal M. Hoffman
Published October 1, 2013
Citation Information: J Clin Invest. 2013;123(11):4695-4705. https://doi.org/10.1172/JCI71543.
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Research Article Immunology Article has an altmetric score of 13

Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies

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Abstract

The inflammasome is a cytoplasmic multiprotein complex that promotes proinflammatory cytokine maturation in response to host- and pathogen-derived signals. Missense mutations in cryopyrin (NLRP3) result in a hyperactive inflammasome that drives overproduction of the proinflammatory cytokines IL-1β and IL-18, leading to the cryopyrin-associated periodic syndromes (CAPS) disease spectrum. Mouse lines harboring CAPS-associated mutations in Nlrp3 have elevated levels of IL-1β and IL-18 and closely mimic human disease. To examine the role of inflammasome-driven IL-18 in murine CAPS, we bred Nlrp3 mutations onto an Il18r-null background. Deletion of Il18r resulted in partial phenotypic rescue that abolished skin and visceral disease in young mice and normalized serum cytokines to a greater extent than breeding to Il1r-null mice. Significant systemic inflammation developed in aging Nlrp3 mutant Il18r-null mice, indicating that IL-1 and IL-18 drive pathology at different stages of the disease process. Ongoing inflammation in double-cytokine knockout CAPS mice implicated a role for caspase-1–mediated pyroptosis and confirmed that CAPS is inflammasome dependent. Our results have important implications for patients with CAPS and residual disease, emphasizing the need to explore other NLRP3-mediated pathways and the potential for inflammasome-targeted therapy.

Authors

Susannah D. Brydges, Lori Broderick, Matthew D. McGeough, Carla A. Pena, James L. Mueller, Hal M. Hoffman

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Figure 5

Aging mutant CAPS mice on IL-18R knockout background develop systemic inflammation.

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Aging mutant CAPS mice on IL-18R knockout background develop systemic in...
(A) Extended survival and (B) growth of MWS Il18r–/–, Il18r–/–, MWS Il1r–/–, and Il1r–/– mice (n = 7–46 for survival and 1–38 for growth, mean ± SEM). Statistical significance was tested by log-rank (Mantel-Cox) comparison. (C) Complete peripheral blood counts for MWS Il1r–/– and Il18r–/– mice at 16 weeks of age (n ≥ 3 mice; each graph point represents 1 mouse, with mean identified by horizontal bar). (D) Spleens from MWS Il18r–/–, Il18r–/–, MWS Il1r–/–, Il11r–/–, and WT littermates were weighed at 8 or 15 weeks (n = 3–12 mice; each graph point represents 1 mouse, with mean identified by horizontal bar). *P < 0.05, **P < 0.005, by Student’s t test. WBC, white blood cells; RBC, red blood cells; ANC, absolute neutrophil count.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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