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Pro-inflammatory properties of H-ferritin on human macrophages, ex vivo and in vitro observations

Authors
  • Ruscitti, Piero1
  • Di Benedetto, Paola2
  • Berardicurti, Onorina1
  • Panzera, Noemi2
  • Grazia, Nicolò2
  • Lizzi, Anna Rita2
  • Cipriani, Paola1
  • Shoenfeld, Yehuda3, 4, 5
  • Giacomelli, Roberto1
  • 1 University of L’Aquila, Delta 6 Building, Via dell’Ospedale, L’Aquila, 67100, Italy , L’Aquila (Italy)
  • 2 University of L’Aquila, L’Aquila, Italy , L’Aquila (Italy)
  • 3 Sheba Medical Center, Tel HaShomer, Israel , Tel HaShomer (Israel)
  • 4 Tel-Aviv University, Tel Aviv, Israel , Tel Aviv (Israel)
  • 5 Saint Petersburg State University, Saint Petersburg, Russia , Saint Petersburg (Russia)
Type
Published Article
Journal
Scientific Reports
Publisher
Springer Nature
Publication Date
Jul 22, 2020
Volume
10
Issue
1
Identifiers
DOI: 10.1038/s41598-020-69031-w
Source
Springer Nature
License
Green

Abstract

Ferritin is an iron-binding molecule, which comprises 24 subunits, heavy (FeH) and light (FeL) subunits, suggested to have a pathogenic role by the ‘hyperferritinemic syndrome’. In this work, we tested (1) FeH and FeL in bone marrow (BM) and sera in patients with macrophage activation syndrome (MAS); (2) pro-inflammatory effects of ferritin, FeL, and FeH on macrophages; (3) ability of FeH-stimulated macrophages to stimulate the proliferation of peripheral blood mononuclear cells (PBMCs); (4) production of mature IL-1β and IL-12p70 in extracellular compartments of FeH-stimulated macrophages. Immunofluorescence analysis and liquid chromatography mass spectrometry (LC–MS/MS) based proteomics were performed to identify FeL and FeH in BM and sera, respectively, in the same patients. Macrophages were stimulated with ferritin, FeH, and FeL to assess pro-inflammatory effects by RT-PCR and western blot. The proliferation of co-cultured PBMCs with FeH-stimulated macrophages was tested. Immunofluorescence showed an increased FeH expression in BMs, whereas LC–MS/MS identified that FeL was mainly represented in sera. FeH induced a significant increase of gene expressions of IL-1β, IL-6, IL-12, and TNF-α, more marked with FeH, which also stimulated NLRP3. FeH-stimulated macrophages enhanced the proliferation of PBMCs. The ELISA assays showed that mature form of IL-1β and IL-12p70 were increased, in extracellular compartments of FeH-stimulated macrophages. Our results showed FeH in BM biopsies of MAS patients, whereas, LC–MS/MS identified FeL in the sera. FeH showed pro-inflammatory effects on macrophages, stimulated NLRP3, and increased PBMCs proliferation.

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