TY - JOUR
T1 - Gut bacteria drive kupffer cell expansion via MAMP-mediated ICAM-1 induction on sinusoidal endothelium and influence preservation-reperfusion injury after orthotopic liver transplantation
AU - Corbitt, Natasha
AU - Kimura, Shoko
AU - Isse, Kumiko
AU - Specht, Susan
AU - Chedwick, Lisa
AU - Rosborough, Brian R.
AU - Lunz, John G.
AU - Murase, Noriko
AU - Yokota, Shinichiro
AU - Demetris, Anthony J.
N1 - Funding Information:
Supported by NIH/National Institute of Diabetes and Digestive and Kidney Diseases grants F31DK089902-01 (N.C.) and PO1 A1081678 (A.J.D.), the Thomas E. Starzl Transplant Endowment Fund (A.J.D.), and University of North Carolina grant P30 DK34987 , Center for Gastrointestinal Biology and Disease (CGIBD) core support. Cl2MDP was a gift from Roche Diagnostics GmbH (Mannheim, Germany).
PY - 2013/1
Y1 - 2013/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajpath.2012.09.010
DO - 10.1016/j.ajpath.2012.09.010
M3 - Article
C2 - 23159949
AN - SCOPUS:84871305315
SN - 0002-9440
VL - 182
SP - 180
EP - 191
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 1
ER -