title: The spleen as an extramedullary source of inflammatory cells responding to acetaminophen-induced liver injury.
abstract: Macrophages have been shown to play a role in acetaminophen (APAP)-induced hepatotoxicity, contributing to both pro- and anti-inflammatory processes. In these studies, we analyzed the role of the spleen as an extramedullary source of hepatic macrophages. APAP administration (300mg/kg, i.p.) to control mice resulted in an increase in CD11b(+) infiltrating Ly6G(+) granulocytic and Ly6G(-) monocytic cells in the spleen and the liver. The majority of the Ly6G(+) cells were also positive for the monocyte/macrophage activation marker, Ly6C, suggesting a myeloid derived suppressor cell (MDSC) phenotype. By comparison, Ly6G(-) cells consisted of 3 subpopulations expressing high, intermediate, and low levels of Ly6C. Splenectomy was associated with increases in mature (F4/80(+)) and immature (F4/80(-)) pro-inflammatory Ly6C(hi) macrophages and mature anti-inflammatory (Ly6C(lo)) macrophages in the liver after APAP; increases in MDSCs were also noted in the livers of splenectomized (SPX) mice after APAP. This was associated with increases in APAP-induced expression of chemokine receptors regulating pro-inflammatory (CCR2) and anti-inflammatory (CX3CR1) macrophage trafficking. In contrast, APAP-induced increases in pro-inflammatory galectin-3(+) macrophages were blunted in livers of SPX mice relative to control mice, along with hepatic expression of TNF-α, as well as the anti-inflammatory macrophage markers, FIZZ-1 and YM-1. These data demonstrate that multiple subpopulations of pro- and anti-inflammatory cells respond to APAP-induced injury, and that these cells originate from distinct hematopoietic reservoirs.
authors.affiliation: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA. Electronic address: milimandal@gmail.com.
authors.forename: Mili
authors.initials: M
authors.lastname: Mandal
authors.affiliation: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA. Electronic address: cgardner@pharmacy.rutgers.edu.
authors.forename: Carol R
authors.initials: CR
authors.lastname: Gardner
authors.affiliation: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA. Electronic address: fishpower52@gmail.com.
authors.forename: Richard
authors.initials: R
authors.lastname: Sun
authors.affiliation: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA. Electronic address: choi@eohsi.rutgers.edu.
authors.forename: Hyejeong
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA. Electronic address: sonurose92@gmail.com.
authors.forename: Sonali
authors.initials: S
authors.lastname: Lad
authors.affiliation: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA. Electronic address: mishinv@eohsi.rutgers.edu.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Mishin
authors.affiliation: Department of Environmental and Occupational Health, School of Public Health, Rutgers University, Piscataway, NJ 08854, USA. Electronic address: jlaskin@eohsi.rutgers.edu.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Laskin
authors.affiliation: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA. Electronic address: laskin@eohsi.rutgers.edu.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Laskin
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D056486:Chemical and Drug Induced Liver Injury / Q000503:physiopathology*; D018925:Chemokines / Q000096:biosynthesis; D037502:Galectin 3 / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects; D022423:Myeloid Cells / Q000187:drug effects*; D010641:Phenotype; D054390:Receptors, CCR2 / Q000096:biosynthesis; D019707:Receptors, Chemokine / Q000096:biosynthesis; D013154:Spleen / Q000378:metabolism*; D013156:Splenectomy
chemical_list: D000073883:CX3C Chemokine Receptor 1; C515335:Ccr2 protein, mouse; D018925:Chemokines; C471885:Cx3cr1 protein, mouse; D037502:Galectin 3; D018836:Inflammation Mediators; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D000082:Acetaminophen
keywords: Acetaminophen; Hepatotoxicity; Macrophages; Myeloid derived suppressor cells; Spleen