Drs. Narayan and Pazar contributed equally to this work.
Octacalcium phosphate crystals induce inflammation in vivo through interleukin-1 but independent of the NLRP3 inflammasome in mice
Article first published online: 28 JAN 2011
Copyright © 2011 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 63, Issue 2, pages 422–433, February 2011
How to Cite
Narayan, S., Pazar, B., Ea, H.-K., Kolly, L., Bagnoud, N., Chobaz, V., Lioté, F., Vogl, T., Holzinger, D., Kai-Lik So, A. and Busso, N. (2011), Octacalcium phosphate crystals induce inflammation in vivo through interleukin-1 but independent of the NLRP3 inflammasome in mice. Arthritis & Rheumatism, 63: 422–433. doi: 10.1002/art.30147
- Issue published online: 28 JAN 2011
- Article first published online: 28 JAN 2011
- Accepted manuscript online: 15 NOV 2010 12:00PM EST
- Manuscript Accepted: 4 NOV 2010
- Manuscript Received: 3 MAY 2010
- Fonds National Suisse de la Recherche Scientifique. Grant Number: 310030-130085/1
- Jean and Linette Warnery Foundation
- Fondation pour la Recherche Médicale
- Association pour la Recherche en Pathologie Synoviale
- Association Rhumatisme et Travail
- German Ministry of Education and Research. Grant Number: BMBF project AID-NET
To determine the mechanisms involved in inflammatory responses to octacalcium phosphate (OCP) crystals in vivo.
OCP crystal–induced inflammation was monitored using a peritoneal model of inflammation in mice with different deficiencies affecting interleukin-1 (IL-1) secretion (IL-1α–/–, IL-1β–/–, ASC–/–, and NLRP3–/– mice) or in mice pretreated with IL-1 inhibitors (anakinra [recombinant IL-1 receptor antagonist] and anti–IL-1β). The production of IL-1α, IL-1β, and myeloid-related protein 8 (MRP-8)–MRP-14 complex was determined by enzyme-linked immunosorbent assay. Peritoneal neutrophil recruitment and cell viability were determined by flow cytometry. Depletion of mast cells or resident macrophages was performed by pretreatment with compound 48/80 or clodronate liposomes, respectively.
OCP crystals induced peritoneal inflammation, as demonstrated by neutrophil recruitment and up-modulation of IL-1α, IL-1β, and MRP-8–MRP-14 complex, to levels comparable with those induced by monosodium urate monohydrate crystals. This OCP crystal–induced inflammation was both IL-1α– and IL-1β–dependent, as shown by the inhibitory effects of anakinra and anti–IL-1β antibody treatment. Accordingly, OCP crystal stimulation resulted in milder inflammation in IL-1α–/– and IL-1β–/– mice. Interestingly, ASC–/– and NLRP3–/– mice did not show any alteration in their inflammation status in response to OCP crystals. Depletion of the resident macrophage population resulted in a significant decrease in crystal-induced neutrophil infiltration and proinflammatory cytokine production in vivo, whereas mast cell depletion had no effect. Finally, OCP crystals induced apoptosis/necrosis of peritoneal cells in vivo.
These data indicate that macrophages, rather than mast cells, are important for initiating and driving OCP crystal–induced inflammation. Additionally, OCP crystals induce IL-1–dependent peritoneal inflammation without requiring the NLRP3 inflammasome.