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.
Highlights
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’
The results showed the presence of FeH in bone marrow (BM) biopsies of Adult-onset Still’s disease (AOSD) patients complicated with macrophage activation syndrome (MAS) patients, whereas FeL was the predominant form in the sera of those
Taking together all these results and considering that AOSD and MAS could be included in the so-called “hyperferritinaemic syndrome”[14], our data could reinforce the hypothesis that higher levels of ferritin may be considered a consequence or an epiphenomenon of the inflammation, but it may actively play a role in pathogenic mechanisms of those diseases, enhancing the inflammatory burden
Summary
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’. 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 FeHstimulated 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. FeH showed pro-inflammatory effects on macrophages, stimulated NLRP3, and increased PBMCs proliferation. The main modulator of this molecules is the iron availability, ferritin synthesis may be regulated by different inflammatory cytokines[17], suggesting a possible role in inflammation[18,19] On these bases, in this work, we aimed at assessing the presence of FeH and FeL in bone marrow (BM) biopsies of patients with AOSD and complicated with MAS. We checked the ability of macrophages, which were stimulated with these molecules, to enhance or not the proliferation of peripheral blood mononuclear cells (PBMCs) and the production of mature IL-1β and IL-12p70 in extracellular compartments of FeH-stimulated macrophages
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