RAGE limits regeneration after massive liver injury by coordinated suppression of TNF-alpha and NF-kappaB.
The exquisite ability of the liver to regenerate is finite. Identification of mechanisms that limit regeneration after massive injury holds the key to expanding the limits of liver transplantation and salvaging livers and hosts overwhelmed by carcinoma and toxic insults. Receptor for advanced glycation endproducts (RAGE) is up-regulated in liver remnants selectively after massive (85%) versus partial (70%) hepatectomy, principally in mononuclear phagocyte-derived dendritic cells (MPDDCs). Blockade of RAGE, using pharmacological antagonists or transgenic mice in which a signaling-deficient RAGE mutant is expressed in cells of mononuclear phagocyte lineage, significantly increases survival after massive liver resection. In the first hours after massive resection, remnants retrieved from RAGE-blocked mice displayed increased activated NF-kappaB, principally in hepatocytes, and enhanced expression of regeneration-promoting cytokines, TNF-alpha and IL-6, and the antiinflammatory cytokine, IL-10. Hepatocyte proliferation was increased by RAGE blockade, in parallel with significantly reduced apoptosis. These data highlight central roles for RAGE and MPDDCs in modulation of cell death-promoting mechanisms in massive hepatectomy and suggest that RAGE blockade is a novel strategy to promote regeneration in the massively injured liver.
Cataldegirmen
Guellue
G
Division of Liver Diseases and Transplantation, Department of Surgery, Columbia University Medical Center, Columbia University, New York, NY 10032, USA.
Zeng
Shan
S
Feirt
Nikki
N
Ippagunta
Nikalesh
N
Dun
Hao
H
Qu
Wu
W
Lu
Yan
Y
Rong
Ling Ling
LL
Hofmann
Marion A
MA
Kislinger
Thomas
T
Pachydaki
Sophia I
SI
Jenkins
Daniel G
DG
Weinberg
Alan
A
Lefkowitch
Jay
J
Rogiers
Xavier
X
Yan
Shi Fang
SF
Schmidt
Ann Marie
AM
Emond
Jean C
JC
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019070:Cell Lineage; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D006498:Hepatectomy; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016207:Cytokines; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha