H-ferritin and proinflammatory cytokines are increased in the bone marrow of patients affected by macrophage activation syndrome

Abstract

Macrophage activation syndrome (MAS) is hyperinflammatory life-threatening syndrome, associated typically with high levels of serum ferritin. This is an iron storage protein including heavy (H) and light (L) subunits, categorized on their molecular weight. The H-/L subunits ratio may be different in tissues, depending on the specific tissue and pathophysiological status. In this study, we analysed the bone marrow (BM) biopsies of adult MAS patients to assess the presence of: (i) H-ferritin and L-ferritin; (ii) CD68 /H-ferritin and CD68 /L-ferritin ; and (iii) interleukin (IL)-1β, tumour necrosis factor (TNF) and interferon (IFN)-γ. We also explored possible correlations of these results with clinical data. H-ferritin, IL-1β, TNF and IFN-γ were increased significantly in MAS. Furthermore, an increased number of CD68 /H-ferritin cells and an infiltrate of cells co-expressing H-ferritin and IL-12, suggesting an infiltrate of M1 macrophages, were observed. H-ferritin levels and CD68 /H-ferritin cells were correlated with haematological involvement of the disease, serum ferritin and C-reactive protein. L-ferritin and CD68 /L-ferritin cells did not correlate with these parameters. In conclusion, during MAS, H-ferritin, CD68 /H-ferritin cells and proinflammatory cytokines were increased significantly in the BM inflammatory infiltrate, pointing out a possible vicious pathogenic loop. To date, H-ferritin and CD68 /H-ferritin were associated significantly with haematological involvement of the disease, suggesting biomarkers assessing severity of clinical picture.

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

“…Our results showed that FeH was more represented than FeL in BM biopsies of patients with AOSD and MAS, as previously reported in affected tissues 18,19,23,24 . Conversely, in sera of these patients, FeL was the predominant form, as reported by LC-MS/MS.…”

“…Taking together these results and previous observations [51][52][53][54] , it could be possible to hypothesize that the stimulation with FeH could orientate the macrophages toward an M1 phenotype, suggesting the need of further studies to entirely clarify these issues. In addition, in inflammatory infiltrate of AOSD and MAS, a specific subset of macrophages was reported, displaying a specific CD68/H-ferritin phenotype expressing IL-12, which cannot be observed in normal tissues 19,23 . Finally, considering that the protein expressions did not confirmed the gene expressions observed following stimulation with ferritin on pro-inflammatory mediators, it could be possible to attribute the pro-inflammatory effects to FeH subunits of the ferritin.…”

Ferritin and C-reactive protein are predictive biomarkers of mortality and macrophage activation syndrome in adult onset Still’s disease. Analysis of the multicentre Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort

“…In this context, hyperferritinaemia plays an important role in the differentiation of MAS from other forms of HLH [36,39]. Furthermore, the expression of ferritin, in bone marrow of patients with AOSD and MAS, correlates with peripheral blood cytopenias and severity [40,41]. Moreover, AOSD and MAS have been included under the so-called 'hyperferritinemic syndrome' in which the pro-inflammatory proprieties of ferritin could be exacerbated in contributing to the inflammatory burden and development of a cytokine storm [18,41].…”

Modulation of Iron Metabolism in Response to Infection: Twists for All Tastes

“…The exact role of the serum ferritin, and the mechanism triggering its release into circulation, during inflammatory conditions, are not known. Some controversy persists as to the role of ferritin in inflammation, with some authors defending that ferritin has an anti-inflammatory effect and others claiming that ferritin is pro-inflammatory [ 67 , 72 ].…”