Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies
Susannah D. Brydges, Lori Broderick, Matthew D. McGeough, Carla A. Pena, James L. Mueller, Hal M. Hoffman
Susannah D. Brydges, Lori Broderick, Matthew D. McGeough, Carla A. Pena, James L. Mueller, Hal M. Hoffman
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Research Article Immunology

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

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 1

Myeloid cells expressing mutant NLRP3 proteins secrete IL-18.

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Myeloid cells expressing mutant NLRP3 proteins secrete IL-18. Tamoxifen-...
Tamoxifen-treated MWS CreT, FCAS CreT, and littermate WT BMDCs were incubated with pure LPS, with and without ATP at (A) 37°C or (B) 32°C. IL-18 in the supernatants was measured by ELISA (n = 4, mean and SEM). Tamoxifen-treated MWS CreT and FCAS CreT peritoneal macrophages (PM) were incubated at 32°C, and (C) IL-1β and (D) IL-18 were measured in the supernatants by ELISA (n = 2, mean and SEM). (E) Adherent monocytes from patients with FCAS were incubated at 37°C or 32°C, and IL-18 was measured in the culture supernatants by ELISA (n = 10). *P < 0.05, **P < 0.005, by Student’s t test.