title: Gut bacteria drive Kupffer cell expansion via MAMP-mediated ICAM-1 induction on sinusoidal endothelium and influence preservation-reperfusion injury after orthotopic liver transplantation.
abstract: Bacteria in the gut microbiome shed microbial-associated molecule patterns (MAMPs) into the portal venous circulation, where they augment various aspects of systemic immunity via low-level stimulation. Because the liver is immediately downstream of the intestines, we proposed that gut-derived MAMPs shape liver immunity and affect Kupffer cell (KC) phenotype. Germ-free (GF), antibiotic-treated (AVMN), and conventional (CL) mice were used to study KC development, function, and response to the significant stress of cold storage, reperfusion, and orthotopic transplantation. We found that a cocktail of physiologically active MAMPs translocate into the portal circulation, with flagellin (Toll-like receptor 5 ligand) being the most plentiful and capable of promoting hepatic monocyte influx in GF mice. In MAMP-deficient GF or AVMN livers, KCs are lower in numbers, have higher phagocytic activity, and have lower major histocompatibility complex II expression. MAMP-containing CL livers harbor significantly increased KC numbers via induction of intercellular adhesion molecule 1 on liver sinusoidal endothelium. These CL KCs have a primed yet expected phenotype, with increased major histocompatibility complex class II and lower phagocytic activity that increases susceptibility to liver preservation/reperfusion injury after orthotopic transplantation. The KC number, functional activity, and maturational status are directly related to the concentration of gut-derived MAMPs and can be significantly reduced by broad-spectrum antibiotics, thereby affecting susceptibility to injury.
authors.affiliation: Division of Transplantation, Department of Pathology, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Corbitt
authors.forename: Shoko
authors.initials: S
authors.lastname: Kimura
authors.forename: Kumiko
authors.initials: K
authors.lastname: Isse
authors.forename: Susan
authors.initials: S
authors.lastname: Specht
authors.forename: Lisa
authors.initials: L
authors.lastname: Chedwick
authors.forename: Brian R
authors.initials: BR
authors.lastname: Rosborough
authors.forename: John G
authors.initials: JG
authors.lastname: Lunz
authors.forename: Noriko
authors.initials: N
authors.lastname: Murase
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Yokota
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Demetris
mesh_terms: D000818:Animals; D001419:Bacteria / Q000302:isolation & purification / Q000378:metabolism*; D018988:Bacterial Translocation / Q000502:physiology; D002432:Cecum / Q000382:microbiology / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism; D005856:Germ-Free Life; D006023:Glycoproteins / Q000096:biosynthesis; D016130:Immunophenotyping; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D007422:Intestines / Q000382:microbiology*; D007728:Kupffer Cells / Q000276:immunology / Q000502:physiology*; D008099:Liver / Q000276:immunology / Q000378:metabolism; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D026901:Membrane Transport Proteins; D054892:Metagenome; D051379:Mice; D010587:Phagocytosis; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology* / Q000473:pathology
chemical_list: D006023:Glycoproteins; D018799:Intercellular Adhesion Molecule-1; D026901:Membrane Transport Proteins; D051192:Receptors, Pattern Recognition; C492273:LYVE1 protein, mouse