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Complement Alternative Pathway Activation in Human Nonalcoholic Steatohepatitis
The innate immune system plays a major role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Recently we reported complement activation in human NASH. However, it remained unclear whether the alternative pathway of complement, which amplifies C3 activation and which is frequently associat...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192551/ https://www.ncbi.nlm.nih.gov/pubmed/25299043 http://dx.doi.org/10.1371/journal.pone.0110053 |
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author | Segers, Filip M. Verdam, Froukje J. de Jonge, Charlotte Boonen, Bas Driessen, Ann Shiri-Sverdlov, Ronit Bouvy, Nicole D. Greve, Jan Willem M. Buurman, Wim A. Rensen, Sander S. |
author_facet | Segers, Filip M. Verdam, Froukje J. de Jonge, Charlotte Boonen, Bas Driessen, Ann Shiri-Sverdlov, Ronit Bouvy, Nicole D. Greve, Jan Willem M. Buurman, Wim A. Rensen, Sander S. |
author_sort | Segers, Filip M. |
collection | PubMed |
description | The innate immune system plays a major role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Recently we reported complement activation in human NASH. However, it remained unclear whether the alternative pathway of complement, which amplifies C3 activation and which is frequently associated with pathological complement activation leading to disease, was involved. Here, alternative pathway components were investigated in liver biopsies of obese subjects with healthy livers (n = 10) or with NASH (n = 12) using quantitative PCR, Western blotting, and immunofluorescence staining. Properdin accumulated in areas where neutrophils surrounded steatotic hepatocytes, and colocalized with the C3 activation product C3c. C3 activation status as expressed by the C3c/native C3 ratio was 2.6-fold higher (p<0.01) in subjects with NASH despite reduced native C3 concentrations (0.94±0.12 vs. 0.57±0.09; p<0.01). Hepatic properdin levels positively correlated with levels of C3c (r(s) = 0.69; p<0.05) and C3c/C3 activation ratio (r(s) = 0.59; p<0.05). C3c, C3 activation status (C3c/C3 ratio) and properdin levels increased with higher lobular inflammation scores as determined according to the Kleiner classification (C3c: p<0.01, C3c/C3 ratio: p<0.05, properdin: p<0.05). Hepatic mRNA expression of factor B and factor D did not differ between subjects with healthy livers and subjects with NASH (factor B: 1.00±0.19 vs. 0.71±0.07, p = 0.26; factor D: 1.00±0.21 vs. 0.66±0.14, p = 0.29;). Hepatic mRNA and protein levels of Decay Accelerating Factor tended to be increased in subjects with NASH (mRNA: 1.00±0.14 vs. 2.37±0.72; p = 0.22; protein: 0.51±0.11 vs. 1.97±0.67; p = 0.28). In contrast, factor H mRNA was downregulated in patients with NASH (1.00±0.09 vs. 0.71±0.06; p<0.05) and a similar trend was observed with hepatic protein levels (1.12±0.16 vs. 0.78±0.07; p = 0.08). Collectively, these data suggest a role for alternative pathway activation in driving hepatic inflammation in NASH. Therefore, alternative pathway factors may be considered attractive targets for treating NASH by inhibiting complement activation. |
format | Online Article Text |
id | pubmed-4192551 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-41925512014-10-14 Complement Alternative Pathway Activation in Human Nonalcoholic Steatohepatitis Segers, Filip M. Verdam, Froukje J. de Jonge, Charlotte Boonen, Bas Driessen, Ann Shiri-Sverdlov, Ronit Bouvy, Nicole D. Greve, Jan Willem M. Buurman, Wim A. Rensen, Sander S. PLoS One Research Article The innate immune system plays a major role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Recently we reported complement activation in human NASH. However, it remained unclear whether the alternative pathway of complement, which amplifies C3 activation and which is frequently associated with pathological complement activation leading to disease, was involved. Here, alternative pathway components were investigated in liver biopsies of obese subjects with healthy livers (n = 10) or with NASH (n = 12) using quantitative PCR, Western blotting, and immunofluorescence staining. Properdin accumulated in areas where neutrophils surrounded steatotic hepatocytes, and colocalized with the C3 activation product C3c. C3 activation status as expressed by the C3c/native C3 ratio was 2.6-fold higher (p<0.01) in subjects with NASH despite reduced native C3 concentrations (0.94±0.12 vs. 0.57±0.09; p<0.01). Hepatic properdin levels positively correlated with levels of C3c (r(s) = 0.69; p<0.05) and C3c/C3 activation ratio (r(s) = 0.59; p<0.05). C3c, C3 activation status (C3c/C3 ratio) and properdin levels increased with higher lobular inflammation scores as determined according to the Kleiner classification (C3c: p<0.01, C3c/C3 ratio: p<0.05, properdin: p<0.05). Hepatic mRNA expression of factor B and factor D did not differ between subjects with healthy livers and subjects with NASH (factor B: 1.00±0.19 vs. 0.71±0.07, p = 0.26; factor D: 1.00±0.21 vs. 0.66±0.14, p = 0.29;). Hepatic mRNA and protein levels of Decay Accelerating Factor tended to be increased in subjects with NASH (mRNA: 1.00±0.14 vs. 2.37±0.72; p = 0.22; protein: 0.51±0.11 vs. 1.97±0.67; p = 0.28). In contrast, factor H mRNA was downregulated in patients with NASH (1.00±0.09 vs. 0.71±0.06; p<0.05) and a similar trend was observed with hepatic protein levels (1.12±0.16 vs. 0.78±0.07; p = 0.08). Collectively, these data suggest a role for alternative pathway activation in driving hepatic inflammation in NASH. Therefore, alternative pathway factors may be considered attractive targets for treating NASH by inhibiting complement activation. Public Library of Science 2014-10-09 /pmc/articles/PMC4192551/ /pubmed/25299043 http://dx.doi.org/10.1371/journal.pone.0110053 Text en © 2014 Segers et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Segers, Filip M. Verdam, Froukje J. de Jonge, Charlotte Boonen, Bas Driessen, Ann Shiri-Sverdlov, Ronit Bouvy, Nicole D. Greve, Jan Willem M. Buurman, Wim A. Rensen, Sander S. Complement Alternative Pathway Activation in Human Nonalcoholic Steatohepatitis |
title | Complement Alternative Pathway Activation in Human Nonalcoholic Steatohepatitis |
title_full | Complement Alternative Pathway Activation in Human Nonalcoholic Steatohepatitis |
title_fullStr | Complement Alternative Pathway Activation in Human Nonalcoholic Steatohepatitis |
title_full_unstemmed | Complement Alternative Pathway Activation in Human Nonalcoholic Steatohepatitis |
title_short | Complement Alternative Pathway Activation in Human Nonalcoholic Steatohepatitis |
title_sort | complement alternative pathway activation in human nonalcoholic steatohepatitis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192551/ https://www.ncbi.nlm.nih.gov/pubmed/25299043 http://dx.doi.org/10.1371/journal.pone.0110053 |
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