Soluble and particulate Co-Cr-Mo alloy implant metals activate the inflammasome danger signaling pathway in human macrophages: a novel mechanism for implant debris reactivity.
Immune reactivity to soluble and particulate implant debris remains the primary cause of aseptic inflammation and implant loosening. However, the intracellular mechanisms that trigger immune cells to sense and respond to exogenous nonbiological agents such as metal particles or metal ions released from orthopedic implants remain unknown. Recent studies in immunology have outlined the importance of the intracellular inflammasome complex of proteins in sensing danger/stress signals triggered by nonbiological agents in the cytosol of macrophages. We hypothesized that metal implant debris can activate the inflammasome pathway in macrophages that causes caspase-1-induced cleavage of intracellular pro-IL-1beta into its mature form, resulting in IL-1beta secretion and induction of a broader proinflammatory response. We tested this hypothesis by examining whether soluble cobalt, chromium, molybdenum, and nickel ions and Co-Cr-Mo alloy particles induce inflammasome- mediated macrophage reactivity. Our results demonstrate that these agents stimulate IL-1beta secretion in human macrophages that is inflammasome mediated (i.e., NADPH-, caspase-1-, Nalp3-, and ASC-dependent). Thus, metal ion- and particle-induced activation of the inflammasome in human macrophages provides evidence of a novel pathway of implant debris-induced inflammation, where contact with implant debris is sensed and transduced by macrophages into a proinflammatory response.
Caicedo
Marco S
MS
Department of Immunology, Rush University Medical Center, Chicago, Illinois 60612, USA.
Desai
Ronak
R
McAllister
Kyron
K
Reddy
Anand
A
Jacobs
Joshua J
JJ
Hallab
Nadim J
NJ
D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D002857:Chromium / Q000494:pharmacology; D003035:Cobalt / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism; D007477:Ions / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D008422:Materials Testing; D008982:Molybdenum / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009532:Nickel / Q000494:pharmacology; D011475:Prosthesis Failure; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D012995:Solubility; D014800:Vitallium
D002352:Carrier Proteins; D053583:Interleukin-1beta; D007477:Ions; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017382:Reactive Oxygen Species; D002857:Chromium; D014800:Vitallium; D003035:Cobalt; D009249:NADP; D009532:Nickel; D008982:Molybdenum; D020170:Caspase 1