Octacalcium phosphate crystals induce inflammation in vivo through interleukin-1 but independent of the NLRP3 inflammasome in mice.

Abstract

OBJECTIVE:

To determine the mechanisms involved in inflammatory responses to octacalcium phosphate (OCP) crystals in vivo.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Sharmal Narayan, Borbala Pazar, Borbola Pazar, Hang-Korng Ea, Laeticia Kolly, Nathaliane Bagnoud, Véronique Chobaz, Frédéric Lioté, Thomas Vogl, Dirk Holzinger, Alexander Kai-Lik So, Nathalie Busso
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 63 Issue 2 Pg. 422-33 (Feb 2011) ISSN: 1529-0131 [Electronic] United States
• PMID: 21279999 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 by the American College of Rheumatology.

Chemical References

• Bone Density Conservation Agents
• Bone Substitutes
• Calcium Phosphates
• Carrier Proteins
• Interleukin-1
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Clodronic Acid
• octacalcium phosphate
• p-Methoxy-N-methylphenethylamine

Topics

• Animals
• Bone Density Conservation Agents (pharmacology)
• Bone Substitutes (toxicity)
• Calcium Phosphates (toxicity)
• Carrier Proteins (metabolism)
• Cell Survival (drug effects)
• Clodronic Acid (pharmacology)
• Crystallization
• Disease Models, Animal
• Female
• Injections, Intraperitoneal
• Interleukin-1 (metabolism)
• Macrophages, Peritoneal (drug effects, pathology)
• Male
• Mast Cells (drug effects, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NLR Family, Pyrin Domain-Containing 3 Protein
• Neutrophils (drug effects, pathology)
• Peritoneum (drug effects, pathology)
• Peritonitis (chemically induced, metabolism, pathology)
• p-Methoxy-N-methylphenethylamine (pharmacology)