Liver inflammation abrogates immunological tolerance induced by Kupffer cells
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Liver inflammation abrogates immunological tolerance induced by Kupffer cells. / Heymann, Felix; Peusquens, Julia; Ludwig-Portugall, Isis; Kohlhepp, Marlene; Ergen, Can; Niemietz, Patricia; Martin, Christian; van Rooijen, Nico; Ochando, Jordi C; Randolph, Gwendalyn J; Luedde, Tom; Ginhoux, Florent; Kurts, Christian; Trautwein, Christian; Tacke, Frank.
In: HEPATOLOGY, Vol. 62, No. 1, 07.2015, p. 279-91.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Liver inflammation abrogates immunological tolerance induced by Kupffer cells
AU - Heymann, Felix
AU - Peusquens, Julia
AU - Ludwig-Portugall, Isis
AU - Kohlhepp, Marlene
AU - Ergen, Can
AU - Niemietz, Patricia
AU - Martin, Christian
AU - van Rooijen, Nico
AU - Ochando, Jordi C
AU - Randolph, Gwendalyn J
AU - Luedde, Tom
AU - Ginhoux, Florent
AU - Kurts, Christian
AU - Trautwein, Christian
AU - Tacke, Frank
N1 - © 2015 by the American Association for the Study of Liver Diseases.
PY - 2015/7
Y1 - 2015/7
N2 - UNLABELLED: The liver is essential for inducing immunological tolerance toward harmless antigens to maintain immune system homeostasis. However, the precise cellular mechanisms of tolerance induction against particle-bound antigens, the role of the local hepatic microenvironment, and implications for therapeutic targets in immune-mediated diseases are currently unclear. In order to elucidate cellular mechanisms of tolerance induction in healthy and injured liver, we developed a novel in vivo system combining the systemic delivery of low-dose peptide antigens coupled to inert particles, immunological readouts, and sophisticated intravital multiphoton microscopy-based imaging of liver in mice. We show that liver resident macrophages, Kupffer cells (KCs), but not hepatic monocyte-derived macrophages or dendritic cells (DCs), are the central cellular scavenger for circulating particle-associated antigens in homeostasis. KC-associated antigen presentation induces CD4 T-cell arrest, expansion of naturally occurring Foxp3(+) CD25(+) interleukin-10-producing antigen-specific regulatory T cells (Tregs) and tolerogenic immunity. Particle-associated tolerance induction in the liver protected mice from kidney inflammation in T-cell-mediated glomerulonephritis, indicating therapeutic potential of targeting KC for immune-mediated extrahepatic disorders. Liver inflammation in two independent experimental models of chronic liver injury and fibrosis abrogated tolerance induction and led to an immunogenic reprogramming of antigen-specific CD4 T cells. In injured liver, infiltrating monocyte-derived macrophages largely augment the hepatic phagocyte compartment, resulting in antigen redistribution between myeloid cell populations and, simultaneously, KCs lose signature markers of their tolerogenic phenotype.CONCLUSIONS: Hepatic induction of tissue-protective immunological tolerance against particulate antigens is dependent on KCs as well as on a noninflamed liver microenvironment, thereby providing mechanistic explanations for the clinical observation of immune dysfunction and tolerance break in patients with advanced liver diseases.
AB - UNLABELLED: The liver is essential for inducing immunological tolerance toward harmless antigens to maintain immune system homeostasis. However, the precise cellular mechanisms of tolerance induction against particle-bound antigens, the role of the local hepatic microenvironment, and implications for therapeutic targets in immune-mediated diseases are currently unclear. In order to elucidate cellular mechanisms of tolerance induction in healthy and injured liver, we developed a novel in vivo system combining the systemic delivery of low-dose peptide antigens coupled to inert particles, immunological readouts, and sophisticated intravital multiphoton microscopy-based imaging of liver in mice. We show that liver resident macrophages, Kupffer cells (KCs), but not hepatic monocyte-derived macrophages or dendritic cells (DCs), are the central cellular scavenger for circulating particle-associated antigens in homeostasis. KC-associated antigen presentation induces CD4 T-cell arrest, expansion of naturally occurring Foxp3(+) CD25(+) interleukin-10-producing antigen-specific regulatory T cells (Tregs) and tolerogenic immunity. Particle-associated tolerance induction in the liver protected mice from kidney inflammation in T-cell-mediated glomerulonephritis, indicating therapeutic potential of targeting KC for immune-mediated extrahepatic disorders. Liver inflammation in two independent experimental models of chronic liver injury and fibrosis abrogated tolerance induction and led to an immunogenic reprogramming of antigen-specific CD4 T cells. In injured liver, infiltrating monocyte-derived macrophages largely augment the hepatic phagocyte compartment, resulting in antigen redistribution between myeloid cell populations and, simultaneously, KCs lose signature markers of their tolerogenic phenotype.CONCLUSIONS: Hepatic induction of tissue-protective immunological tolerance against particulate antigens is dependent on KCs as well as on a noninflamed liver microenvironment, thereby providing mechanistic explanations for the clinical observation of immune dysfunction and tolerance break in patients with advanced liver diseases.
KW - Animals
KW - Antigen Presentation
KW - Antigens
KW - Cell Proliferation
KW - Immune Tolerance
KW - Kupffer Cells
KW - Liver
KW - Mice, Inbred C57BL
KW - T-Lymphocytes
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1002/hep.27793
DO - 10.1002/hep.27793
M3 - SCORING: Journal article
C2 - 25810240
VL - 62
SP - 279
EP - 291
JO - HEPATOLOGY
JF - HEPATOLOGY
SN - 0270-9139
IS - 1
ER -
