• Cristina Rosário,
  • Gisele Zandman-Goddard,
  • Esther G Meyron-Holtz,
  • David P D’Cruz and
  • Yehuda ShoenfeldEmail author
BMC Medicine201311:185

DOI: 10.1186/1741-7015-11-185

Received: 18 March 2013

Accepted: 29 July 2013

Published: 22 August 2013

Ferritin and immunity

Ferritin as an immunosuppressant

H-ferritin has immunomodulatory effects, including suppression of the delayed type of hypersensitivity to induce anergy [23], suppression of antibody production by B lymphocytes [24], decreasing the phagocytosis by granulocytes [25], and regulating granulomonocytopoiesis [25]. Nevertheless, another ferritin-like molecule, a cloned human chimeric H-ferritin chain, PLIF (placenta immunomodulator ferritin), suppresses myelopoiesis and T cells, supporting the evidence that H-ferritin may have immunosuppressive functions [26]. The mechanisms underlying the inhibitory functions of H-ferritin are largely unknown, and they may include direct or indirect signaling via specific receptors for H-ferritin on lymphocytes [20] or the down-regulation of CD2, which acts as a cofactor for lymphocyte stimulation [27]. More recent data suggest that H-ferritin may suppress immune responses by its ability to induce production of the anti-inflammatory cytokine IL-10 in lymphocytes [28].

In addition to its suppressive effects on hematopoietic cell proliferation and differentiation, there is also evidence that H-ferritin plays an important role in chemokine receptor signaling and receptor-mediated cell migration. H-ferritin is a negative regulator of the CXC-chemokine receptor 4 (CXCR4). Thus, H-ferritin binding to CXCR4 impairs the signaling leading to the activation of mitogen-activated protein kinase (MAPK), a kinase that is known to play an important role in cell proliferation, differentiation and migration [29].

Ferritin as a pro-inflammatory mediator

A novel role for extracellular ferritin as a pro-inflammatory signaling molecule in hepatic stellate cells has been proposed by Ruddell et al.[30]. Cells treated with ferritin activated a TIM-2-independent pathway comprising PI3 kinase phosphorylation, protein kinase C zeta activation and MAPK activation, ultimately culminating in activation of nuclear factor-κB (NF-κB). Activation of NF-κB in turn enhanced the expression of pro-inflammatory mediators, including IL-1β, inducible nitric oxide synthase and others. Of great relevance is the fact that this function was independent of the iron content of ferritin, suggesting that exogenous ferritin may assume roles entirely independent of its classic role as an iron binding protein. Moreover, this study showed that L-chain-rich tissue ferritin, and recombinant H- and L-ferritin, all initiated the activation of signaling pathways, which clearly suggests a role for serum ferritin (that is constituted mainly of L-ferritin subunits) as a pro-inflammatory mediator. Also, it was proposed that ferritin may play a role in an array of inflammatory/fibrogenic states associated with infection in organs, such as the heart, lungs, kidney and pancreas, all of which have cell types similar to hepatic stellate cells that mediate the fibrogenic response to injury [17, 30].

A comprehensive analysis of the role of ferritin as a signaling molecule via TIM-2, Scara5 or via as yet unidentified receptors, will be of great interest and may lead to a better understanding of the precise role of circulating ferritin in inflammation.

Ferritin in autoimmune diseases

Hyperferritinemia is known to be associated with autoimmune diseases, such as SLE, RA and MS [3, 4, 5, 6, 7], and also in serological antiphospholipid syndrome (APS) [8] (Table 1). The relevance of ferritin in autoimmune diseases is also supported by the finding of autoantibodies against ferritin in different autoimmune diseases: RA [31], giant cell arteritis and polymyalgia rheumatica [32] and Takayasu arteritis [33]. Yet, their importance remains to be established.


 There is increasing evidence that circulating ferritin levels may not only reflect an acute phase response but may play a critical role in inflammation.

 MAS, AOSD, cAPS and septic shock are associated with very high levels of ferritin.

 These disorders share similar clinical and laboratory presentations and respond to similar treatments, suggesting that hyperferritinemia may be involved in a common pathogenic mechanism.

 We hypothesize that the huge levels of ferritin seen in these four clinical conditions are not just a secondary product of the inflammatory process, but rather, they are part of the pathogenic mechanism.

 We propose to include these four disorders under a single nomenclature: “The Hyperferritinemic Syndrome”.

So what we have here is a very complex physiology regarding ferritin; “more to be revealed” I’ve seen patients with all manner of elevations of ferritin, standard teaching has always been that it’s simply “an acute-phase reactant”.  It’s obviously a LOT more, immune suppression & pro-inflammatory effects are contradictory; but there they are!  Ferritin is involved in CONTROL of immune responses in many ways.  CIRS is another complex disorder that we’re constantly learning more about.  Fascinating stuff!

Dr. Raymond Oenbrink