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Erschienen in: Pediatric Rheumatology 1/2013

Open Access 01.11.2013 | Meeting abstract

OR11-004 - IL-1, IL-18 and cell death in NLRP3 driven disease

verfasst von: L Broderick, SD Brydges, MD McGeough, CA Pena, JL Mueller, HM Hoffman

Erschienen in: Pediatric Rheumatology | Sonderheft 1/2013

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Competing interests

L. Broderick: None declared, S. Brydges: None declared, M. McGeough: None declared, C. Pena: None declared, J. Mueller: None declared, H. Hoffman Consultant for: Regeneron, Novartis, Sobi Pharmaceuticals.

Introduction

Missense mutations in cryopyrin (NLRP3) result in a hyperactive inflammasome that drives overproduction of the pro-inflammatory cytokines interleukin-1b (IL-1b) and IL-18. Mice expressing mutations associated with familial cold autoinflammatory syndrome (FCAS) or Muckle-Wells syndrome (MWS) exhibit severe, spontaneous inflammation, early death, and hyperresponsiveness to stimuli in vitro. Abrogating IL-1 signaling either genetically or pharmacologically results in modest improvement of life expectancy in murine CAPS, but clearly indicates a role for players in addition to IL-1b.

Objectives

To examine the role of other caspase-1 dependent mediators, namely IL-18, in the context of inflammasome-mediated disease.

Methods

Mice heterozygous for the A350V MWS mutation or the L351P NOMID mutation were bred to IL-1R-/- or IL-18R-/- knockout mice, and weighed and assessed daily. Bone marrow macrophages and peritoneal cells were evaluated in vitro with inflammatory stimuli. Peripheral blood was drawn for complete blood counts and serum cytokine analyses. Pathology was examined in both young and old mice. Bone marrow transplant experiments were used to elucidate the role of cellular signaling compartments.

Results

Similar to IL-1b, hematopoietic cells derived from our mutant mice and monocytes from FCAS patients hyper-secrete IL-18, in response to low amounts of inflammatory stimuli or cold temperature. Breeding Nlrp3 mutations onto an IL-18R null background 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 IL-1R null mice. However, significant systemic inflammation developed in aging Nlrp3 mutant IL-18R null mice, implicating a role for pyroptosis, a caspase-1 mediated form of cell death. Bone marrow transplant studies demonstrate that hematopoietic cells are driving disease in murine CAPS but signaling requirements differ between IL-1 and IL-18.

Conclusion

These studies demonstrate a previously underappreciated role for IL-18 signaling in murine CAPS pathogenesis. We also confirm our previous findings that CAPS is inflammasome-dependent by demonstrating that intact caspase-1 is required for disease, yet other downstream mechanisms besides IL-18 and IL-1b mediated inflammation are involved in this autoinflammatory syndrome constellation. Our results may have important implications for patients with CAPS and residual disease and emphasize the need to explore other NLRP3 mediated pathways and the potential for inflammasome targeted therapy.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Competing interests

L. Broderick: None declared, S. Brydges: None declared, M. McGeough: None declared, C. Pena: None declared, J. Mueller: None declared, H. Hoffman Consultant for: Regeneron, Novartis, Sobi Pharmaceuticals.
Metadaten
Titel
OR11-004 - IL-1, IL-18 and cell death in NLRP3 driven disease
verfasst von
L Broderick
SD Brydges
MD McGeough
CA Pena
JL Mueller
HM Hoffman
Publikationsdatum
01.11.2013
Verlag
BioMed Central
Erschienen in
Pediatric Rheumatology / Ausgabe Sonderheft 1/2013
Elektronische ISSN: 1546-0096
DOI
https://doi.org/10.1186/1546-0096-11-S1-A193

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