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Factor H uptake regulates intracellular C3 activation during apoptosis and decreases the inflammatory potential of nucleosomes.

Martin, Myriam LU ; Leffler, Jonatan LU ; Smolag, Karolina LU ; Mytych, Jennifer LU ; Björk, Albin LU ; Chaves, L D; Alexander, J J; Quigg, R J and Blom, Anna LU (2016) In Cell Death and Differentiation 23. p.903-911
Abstract
Factor H (FH) binds apoptotic cells to limit the inflammatory potential of complement. Here we report that FH is actively internalized by apoptotic cells to enhance cathepsin L-mediated cleavage of endogenously expressed C3, which results in increased surface opsonization with iC3b. In addition, internalized FH forms complexes with nucleosomes, facilitates their phagocytosis by monocytes and induces an anti-inflammatory biased cytokine profile. A similar cytokine response was noted for apoptotic cells coated with FH, confirming that FH diminishes the immunogenic and inflammatory potential of autoantigens. These findings were supported by in vivo observations from CFH(-/-) MRL-lpr mice, which exhibited higher levels of circulating... (More)
Factor H (FH) binds apoptotic cells to limit the inflammatory potential of complement. Here we report that FH is actively internalized by apoptotic cells to enhance cathepsin L-mediated cleavage of endogenously expressed C3, which results in increased surface opsonization with iC3b. In addition, internalized FH forms complexes with nucleosomes, facilitates their phagocytosis by monocytes and induces an anti-inflammatory biased cytokine profile. A similar cytokine response was noted for apoptotic cells coated with FH, confirming that FH diminishes the immunogenic and inflammatory potential of autoantigens. These findings were supported by in vivo observations from CFH(-/-) MRL-lpr mice, which exhibited higher levels of circulating nucleosomes and necrotic cells than their CFH(+/+) littermates. This unconventional function of FH broadens the established view of apoptotic cell clearance and appears particularly important considering the strong associations with genetic FH alterations and diseases such as systemic lupus erythematosus and age-related macular degeneration.Cell Death and Differentiation advance online publication, 15 January 2016; doi:10.1038/cdd.2015.164. (Less)
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publication status
published
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Cell Death and Differentiation
volume
23
pages
903 - 911
publisher
Nature Publishing Group
external identifiers
  • pmid:26768663
  • scopus:84954409820
  • wos:000374127500015
ISSN
1350-9047
DOI
10.1038/cdd.2015.164
language
English
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yes
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220207cd-b79b-4aa8-b6b9-00d2d926d56e (old id 8589118)
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http://www.ncbi.nlm.nih.gov/pubmed/26768663?dopt=Abstract
date added to LUP
2016-02-03 13:50:49
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2017-10-01 04:55:15
@article{220207cd-b79b-4aa8-b6b9-00d2d926d56e,
  abstract     = {Factor H (FH) binds apoptotic cells to limit the inflammatory potential of complement. Here we report that FH is actively internalized by apoptotic cells to enhance cathepsin L-mediated cleavage of endogenously expressed C3, which results in increased surface opsonization with iC3b. In addition, internalized FH forms complexes with nucleosomes, facilitates their phagocytosis by monocytes and induces an anti-inflammatory biased cytokine profile. A similar cytokine response was noted for apoptotic cells coated with FH, confirming that FH diminishes the immunogenic and inflammatory potential of autoantigens. These findings were supported by in vivo observations from CFH(-/-) MRL-lpr mice, which exhibited higher levels of circulating nucleosomes and necrotic cells than their CFH(+/+) littermates. This unconventional function of FH broadens the established view of apoptotic cell clearance and appears particularly important considering the strong associations with genetic FH alterations and diseases such as systemic lupus erythematosus and age-related macular degeneration.Cell Death and Differentiation advance online publication, 15 January 2016; doi:10.1038/cdd.2015.164.},
  author       = {Martin, Myriam and Leffler, Jonatan and Smolag, Karolina and Mytych, Jennifer and Björk, Albin and Chaves, L D and Alexander, J J and Quigg, R J and Blom, Anna},
  issn         = {1350-9047},
  language     = {eng},
  month        = {01},
  pages        = {903--911},
  publisher    = {Nature Publishing Group},
  series       = {Cell Death and Differentiation},
  title        = {Factor H uptake regulates intracellular C3 activation during apoptosis and decreases the inflammatory potential of nucleosomes.},
  url          = {http://dx.doi.org/10.1038/cdd.2015.164},
  volume       = {23},
  year         = {2016},
}