The hyperferritinemic syndromes and CD163: a marker of macrophage activation.

F erritin is a key protein in iron metabolism. Its involvement in iron detoxification and iron storage is known, but recently, a new role in the pathogenesis of different autoimmune and autoinflammatory syndromes was hypothesized [1]. Four immune mediated conditions sharing the feature of marked hyperferritinemia have been gathered under the single term “Hyperferritinemic Syndromes” [1]. Such syndromes include macrophage activation syndrome (MAS), catastrophic antiphospholipid syndrome (CAPS), septic shock, and adultonset Still’s disease (AOSD). These conditions constitute the scenario of the so-called cytokine storm and share a marked hyperferritinemia as well as clinical and laboratory features. As far as we know, with regard to its structure, ferritin is composed of two different subunits, H and L, whose ratio is not fixed as it varies among several inflammatory and infectious conditions. Ferritin in spleen and liver, as well as in serum, is largely composed of L-subunits (involved in iron storage), while in heart and kidney the H-subunits (involved in iron detoxification) are predominant. Recently, an increase in the H-subunit expression, driven by different inflammatory stimuli, was demonstrated [2]. Furthermore, a possible role for ferritin in the regulation of immune response was suggested by Recalcati et al. in 2008 [3]. Indeed, the H-ferritin subunit can inhibit lymphoid and myeloid cell proliferation; and a specific ferritin receptor named TIM2, present on several immune effector cells in murine models, has been identified [4]. Ruddell et al. reported in 2009 [5] that ferritin may behave similarly to pro-inflammatory cytokines, binding to the TIM-2 receptor in hepatic cell media. In doing so it may activate the hepatic cells, inducing enhanced production of several cytokines such as interleukin (IL)-1β. With regard to its production, ferritin synthesis is induced by several inflammatory stimuli including cytokines IL-1α, IL-1β, IL-18, tumor necrosis factor-alpha (TNFα), interferongamma (IFNγ), macrophage-colony stimulating factor (M-CSF) and IL-6. It was initially believed that the main passive source of ferritin was its leakage from damaged cells during inflammatory conditions. Ghosh et al. [6] later described an active production of ferritin L-subunit through a classical secretory pathway. More recently, Cohen et al. [7] reported the significant contribution of macrophages in ferritin production owing to the proven ability of these cells to actively secrete this protein through a non-classical secretory pathway. Such findings support the idea of active production of ferritin in the course of specific autoinflammatory conditions and, thus, a possible role other than second acute inflammatory reactant.