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Inflammatory but not apoptotic death of granulocytes citrullinates fibrinogen

Overview of attention for article published in Arthritis Research & Therapy, December 2015
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About this Attention Score

  • In the top 25% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (81st percentile)
  • Average Attention Score compared to outputs of the same age and source

Mentioned by

1 news outlet


19 Dimensions

Readers on

34 Mendeley
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Inflammatory but not apoptotic death of granulocytes citrullinates fibrinogen
Published in
Arthritis Research & Therapy, December 2015
DOI 10.1186/s13075-015-0890-0
Pubmed ID

Nathalie E. Blachère, Salina Parveen, John Fak, Mayu O. Frank, Dana E. Orange


Neutrophil activation induces citrullination of intracellular targets of anticitrullinated peptide antibodies (ACPA), which are specific for rheumatoid arthritis (RA). Citrullinated fibrinogen is bound by ACPA but it is less well understood how extracellular proteins are citrullinated. The cells that produce fibrinogen, hepatocytes, do not express peptidyl arginine deiminase (PAD) enzymes nor do PAD enzymes include N-terminal signal peptides to direct them into the secretory pathway. We hypothesized that dying neutrophils release PAD in the extracellular space, and that this could cause citrullination of target extracellular antigens relevant to RA such as fibrinogen. HL60 cells were differentiated into neutrophil-like cells by treatment with all-trans retinoic acid (ATRA). Differentiation was confirmed by CD11b staining, PAD4, PAD2 and myeloperoxidase expression, cell division, and nuclear morphology. Death was induced with various stimuli, including freeze-thaw to induce necrosis, Ionomycin and PMA to induce NETosis, and UV-B to induce apoptosis. Death markers were assessed by immunohistochemistry and flow cytometry. To quantify extracellular citrullination, dying ATRA-differentiated HL60 cells were cultured with fibrinogen for 24 hours and supernatants were probed for fibrinogen citrullination, PAD2 and PAD4 by western blot. While both NETotic and necrotic ATRA differentiated HL60 cells citrullinated fibrinogen, apoptotic cells did not citrullinate fibrinogen, even when allowed to undergo secondary necrosis. Incubation of necrotic neutrophil lysates with fibrinogen also causes fibrinogen citrullination. PAD2 and PAD4 were detected by western blot of supernatants of ATRA-differentiated HL60 cells undergoing necrotic and NETotic death, but not apoptotic or secondarily necrotic cell death. We implicate granulocytes undergoing inflammatory cell death as a mechanism for altering extracellular self-proteins that may be targets of autoimmunity linked to inflammatory diseases such as rheumatoid arthritis.

Mendeley readers

The data shown below were compiled from readership statistics for 34 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Netherlands 1 3%
Unknown 33 97%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 11 32%
Researcher 5 15%
Student > Master 5 15%
Student > Postgraduate 2 6%
Student > Bachelor 2 6%
Other 4 12%
Unknown 5 15%
Readers by discipline Count As %
Medicine and Dentistry 11 32%
Immunology and Microbiology 7 21%
Biochemistry, Genetics and Molecular Biology 5 15%
Chemistry 2 6%
Agricultural and Biological Sciences 1 3%
Other 2 6%
Unknown 6 18%

Attention Score in Context

This research output has an Altmetric Attention Score of 7. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 19 December 2015.
All research outputs
of 12,451,992 outputs
Outputs from Arthritis Research & Therapy
of 1,983 outputs
Outputs of similar age
of 343,008 outputs
Outputs of similar age from Arthritis Research & Therapy
of 315 outputs
Altmetric has tracked 12,451,992 research outputs across all sources so far. Compared to these this one has done well and is in the 83rd percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 1,983 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 6.0. This one has gotten more attention than average, scoring higher than 72% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 343,008 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 81% of its contemporaries.
We're also able to compare this research output to 315 others from the same source and published within six weeks on either side of this one. This one is in the 48th percentile – i.e., 48% of its contemporaries scored the same or lower than it.