Elucidating the role of monocyte-derived hepcidin

To the editor:

Anemia of chronic disease is an important cause of morbidity in patients suffering from chronic inflammatory states and has been rechristened anemia of inflammation with the onset of molecular insights into the pathogenesis of this disease in recent years.¹ 

Theurl and colleagues have shown that hepcidin, the key regulator of systemic iron homeostasis produced chiefly in the hepatocytes and to a lesser extent in circulating monocytes, can cause iron retention within these cells when expressed in higher amounts as during inflammation.²  This corroborates the findings of work done earlier in mice addressing the importance of toll-like receptor 4 (TLR4)–stimulated production of hepcidin in myeloid cells.³ 

However, to truly observe the role of monocyte-derived hepcidin under in vivo conditions, it would require hepatocyte-specific and time-dependent conditional knockout of hepcidin production to note whether interleukin 6 (IL-6) is still able to induce the production of hypoferremia at least locally if not systemically. This is because IL-6 appears to induce hepcidin production both in the monocytes and in the hepatocytes. This for obvious reasons is practical only in a murine model as opposed to humans, but nevertheless important in firmly establishing the concept put forward by the authors.² 

Theurl et al have shown a strong correlation between the levels of serum IL-6 and monocyte hepcidin mRNA levels, but go on to state in their discussion that the sequestration of hepcidin produced by monocytes locally may be of specific importance at inflammatory sites with poor perfusion, such as the interstitium. An important question to consider is the contribution made by production of cytokines by the cells at such sites rather than a systemic correlation to support the statement.

Finally, Theurl et al have not commented on why serum ferritin levels do not correlate with the monocyte hepcidin mRNA levels, though hepcidin causes iron retention within these cells. The above issues need to be addressed to firmly establish the role of monocyte-derived hepcidin in the regulation of iron homeostasis in anemia of chronic disease.