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The C1q-ApoE complex: A new hallmark pathology of viral hepatitis and nonalcoholic fatty liver disease

We recently identified a high-affinity C1q-ApoE complex in human artery atherosclerotic intima lesions and in human amyloid plaques of Alzheimer’s Disease brains defining a common pathogenetic pathway of two diverse diseases, i.e. atherosclerosis and dementia. C1q is the initiating and controlling p...

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Autores principales: Habenicht, Livia K. L., Wang, Zhihua, Zhang, Xi, Li, Yuanfang, Mogler, Carolin, Huspenina, Julia Slotta, Schmid, Roland M., Weber, Christian, Mohanta, Sarajo K., Ma, Zhe, Yin, Changjun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9592549/
https://www.ncbi.nlm.nih.gov/pubmed/36304458
http://dx.doi.org/10.3389/fimmu.2022.970938
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author Habenicht, Livia K. L.
Wang, Zhihua
Zhang, Xi
Li, Yuanfang
Mogler, Carolin
Huspenina, Julia Slotta
Schmid, Roland M.
Weber, Christian
Mohanta, Sarajo K.
Ma, Zhe
Yin, Changjun
author_facet Habenicht, Livia K. L.
Wang, Zhihua
Zhang, Xi
Li, Yuanfang
Mogler, Carolin
Huspenina, Julia Slotta
Schmid, Roland M.
Weber, Christian
Mohanta, Sarajo K.
Ma, Zhe
Yin, Changjun
author_sort Habenicht, Livia K. L.
collection PubMed
description We recently identified a high-affinity C1q-ApoE complex in human artery atherosclerotic intima lesions and in human amyloid plaques of Alzheimer’s Disease brains defining a common pathogenetic pathway of two diverse diseases, i.e. atherosclerosis and dementia. C1q is the initiating and controlling protein of the classical complement cascade (CCC), which occupies a key role in multiple acute and chronic inflammatory tissue responses. C1q is largely produced by myeloid cells including Kupffer cells (KCs) and subsequently secreted into the circulation as an inactive preprotein. Its binding partner, Apolipoprotein E (ApoE), is produced by KCs and hepatocytes and it is also secreted into the circulation, where it regulates essential steps of lipid transport. In addition to its major source, ApoE can be produced by non-liver cells including immune cells and multiple other cells depending on local tissue contexts. To initiate the CCC cascade, C1q must be activated by molecules as varied as oxidized lipids, amyloid fibrils, and immune complexes. However, ApoE is mute towards inactive C1q but binds at high-affinity to its activated form. Specifically, our studies revealed that ApoE is a CCC-specific checkpoint inhibitor via the formation of the C1q-ApoE complex. We proposed that it may arise in multiple if not all CCC-associated diseases and that its presence indicates ongoing CCC activity. Here, we turned to the liver to examine C1q-ApoE complexes in human B- and C-viral hepatitis and nonalcoholic fatty liver disease (NAFLD). In addition, we used multidrug-resistance-2 gene-knockout (Mdr2-KO) mice as a model for inflammatory liver disease and hepatocellular carcinoma (HCC) pathogenesis. In normal murine and human livers, KCs were the major C1q-producing cell type while hepatocytes were the primary ApoE-forming cell type though the C1q-ApoE complex was rare or nonexistent. However, significant numbers of C1q-ApoE complexes formed in both Mdr2-KO, human viral hepatitis, and NAFLD around portal triads where immune cells had infiltrated the liver. Additionally, high numbers of C1q-ApoE complexes emerged in human livers in areas of extracellular lipid droplets across the entire liver parenchyma in NAFLD-affected patients. Thus, the C1q-ApoE complex is a new pathological hallmark of viral hepatitis B and C and NAFLD.
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spelling pubmed-95925492022-10-26 The C1q-ApoE complex: A new hallmark pathology of viral hepatitis and nonalcoholic fatty liver disease Habenicht, Livia K. L. Wang, Zhihua Zhang, Xi Li, Yuanfang Mogler, Carolin Huspenina, Julia Slotta Schmid, Roland M. Weber, Christian Mohanta, Sarajo K. Ma, Zhe Yin, Changjun Front Immunol Immunology We recently identified a high-affinity C1q-ApoE complex in human artery atherosclerotic intima lesions and in human amyloid plaques of Alzheimer’s Disease brains defining a common pathogenetic pathway of two diverse diseases, i.e. atherosclerosis and dementia. C1q is the initiating and controlling protein of the classical complement cascade (CCC), which occupies a key role in multiple acute and chronic inflammatory tissue responses. C1q is largely produced by myeloid cells including Kupffer cells (KCs) and subsequently secreted into the circulation as an inactive preprotein. Its binding partner, Apolipoprotein E (ApoE), is produced by KCs and hepatocytes and it is also secreted into the circulation, where it regulates essential steps of lipid transport. In addition to its major source, ApoE can be produced by non-liver cells including immune cells and multiple other cells depending on local tissue contexts. To initiate the CCC cascade, C1q must be activated by molecules as varied as oxidized lipids, amyloid fibrils, and immune complexes. However, ApoE is mute towards inactive C1q but binds at high-affinity to its activated form. Specifically, our studies revealed that ApoE is a CCC-specific checkpoint inhibitor via the formation of the C1q-ApoE complex. We proposed that it may arise in multiple if not all CCC-associated diseases and that its presence indicates ongoing CCC activity. Here, we turned to the liver to examine C1q-ApoE complexes in human B- and C-viral hepatitis and nonalcoholic fatty liver disease (NAFLD). In addition, we used multidrug-resistance-2 gene-knockout (Mdr2-KO) mice as a model for inflammatory liver disease and hepatocellular carcinoma (HCC) pathogenesis. In normal murine and human livers, KCs were the major C1q-producing cell type while hepatocytes were the primary ApoE-forming cell type though the C1q-ApoE complex was rare or nonexistent. However, significant numbers of C1q-ApoE complexes formed in both Mdr2-KO, human viral hepatitis, and NAFLD around portal triads where immune cells had infiltrated the liver. Additionally, high numbers of C1q-ApoE complexes emerged in human livers in areas of extracellular lipid droplets across the entire liver parenchyma in NAFLD-affected patients. Thus, the C1q-ApoE complex is a new pathological hallmark of viral hepatitis B and C and NAFLD. Frontiers Media S.A. 2022-10-06 /pmc/articles/PMC9592549/ /pubmed/36304458 http://dx.doi.org/10.3389/fimmu.2022.970938 Text en Copyright © 2022 Habenicht, Wang, Zhang, Li, Mogler, Huspenina, Schmid, Weber, Mohanta, Ma and Yin https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Habenicht, Livia K. L.
Wang, Zhihua
Zhang, Xi
Li, Yuanfang
Mogler, Carolin
Huspenina, Julia Slotta
Schmid, Roland M.
Weber, Christian
Mohanta, Sarajo K.
Ma, Zhe
Yin, Changjun
The C1q-ApoE complex: A new hallmark pathology of viral hepatitis and nonalcoholic fatty liver disease
title The C1q-ApoE complex: A new hallmark pathology of viral hepatitis and nonalcoholic fatty liver disease
title_full The C1q-ApoE complex: A new hallmark pathology of viral hepatitis and nonalcoholic fatty liver disease
title_fullStr The C1q-ApoE complex: A new hallmark pathology of viral hepatitis and nonalcoholic fatty liver disease
title_full_unstemmed The C1q-ApoE complex: A new hallmark pathology of viral hepatitis and nonalcoholic fatty liver disease
title_short The C1q-ApoE complex: A new hallmark pathology of viral hepatitis and nonalcoholic fatty liver disease
title_sort c1q-apoe complex: a new hallmark pathology of viral hepatitis and nonalcoholic fatty liver disease
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9592549/
https://www.ncbi.nlm.nih.gov/pubmed/36304458
http://dx.doi.org/10.3389/fimmu.2022.970938
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