title: Cyclophilin A is a damage-associated molecular pattern molecule that mediates acetaminophen-induced liver injury.
abstract: The immune system is alerted to cell death by molecules known as damage-associated molecular patterns (DAMPs). These molecules partly mediate acetaminophen-induced liver injury, an archetypal experimental model of sterile cell death and the commonest cause of acute liver failure in the western world. Cyclophilin A (CypA) is an intracellular protein that is proinflammatory when released by cells. We hypothesized that CypA is released from necrotic liver cells and acts as a DAMP to mediate acetaminophen-induced liver injury. Our data demonstrated that mice lacking CypA (Ppia(-/-)) were resistant to acetaminophen toxicity. Antagonism of the extracellular receptor for CypA (CD147) also reduced acetaminophen-induced liver injury. When injected into a wild-type mouse, necrotic liver from Ppia(-/-) mice induced less of an inflammatory response than did wild-type liver. Conversely, the host inflammatory response was increased when CypA was injected with necrotic liver. Antagonism of CD147 also reduced the inflammatory response to necrotic liver. In humans, urinary CypA concentration was significantly increased in patients with acetaminophen-induced liver injury. In summary, CypA is a DAMP that mediates acetaminophen poisoning. This mechanistic insight presents an opportunity for a new therapeutic approach to a disease that currently has inadequate treatment options.
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, Edinburgh University, Edinburgh, EH16 4TJ United Kingdom. james.dear@ed.ac.uk
authors.forename: James W
authors.initials: JW
authors.lastname: Dear
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Simpson
authors.forename: Melianthe P J
authors.initials: MP
authors.lastname: Nicolai
authors.forename: James H
authors.initials: JH
authors.lastname: Catterson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Street
authors.forename: Tineke
authors.initials: T
authors.lastname: Huizinga
authors.forename: Darren G
authors.initials: DG
authors.lastname: Craig
authors.forename: Kevin
authors.initials: K
authors.lastname: Dhaliwal
authors.forename: Sheila
authors.initials: S
authors.lastname: Webb
authors.forename: D Nicholas
authors.initials: DN
authors.lastname: Bateman
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000378:metabolism; D021984:Cyclophilin A / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D021984:Cyclophilin A