title: 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.
  
  
  CONCLUSIONS
  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.affiliation: Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: Sharmal
authors.initials: S
authors.lastname: Narayan
authors.forename: Borbala
authors.initials: B
authors.lastname: Pazar
authors.forename: Borbola
authors.initials: B
authors.lastname: Pazar
authors.forename: Hang-Korng
authors.initials: HK
authors.lastname: Ea
authors.forename: Laeticia
authors.initials: L
authors.lastname: Kolly
authors.forename: Nathaliane
authors.initials: N
authors.lastname: Bagnoud
authors.forename: Véronique
authors.initials: V
authors.lastname: Chobaz
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lioté
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.forename: Dirk
authors.initials: D
authors.lastname: Holzinger
authors.forename: Alexander
authors.initials: A
authors.lastname: Kai-Lik So
authors.forename: Nathalie
authors.initials: N
authors.lastname: Busso
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D018786:Bone Substitutes / Q000633:toxicity*; D002130:Calcium Phosphates / Q000633:toxicity*; D002352:Carrier Proteins / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004002:Clodronic Acid / Q000494:pharmacology; D003460:Crystallization; D004195:Disease Models, Animal; D005260:Female; D007274:Injections, Intraperitoneal; D007375:Interleukin-1 / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D010537:Peritoneum / Q000187:drug effects / Q000473:pathology; D010538:Peritonitis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
chemical_list: D050071:Bone Density Conservation Agents; D018786:Bone Substitutes; D002130:Calcium Phosphates; D002352:Carrier Proteins; D007375:Interleukin-1; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D004002:Clodronic Acid; C022045:octacalcium phosphate; D003189:p-Methoxy-N-methylphenethylamine