Role of cutaneous hepcidin in graft-versus-host disease (GvHD)

Acute graft-versus-host disease (GVHD) is a major cause of mortality in patients undergoing hematopoietic cell transplantation (HCT) for hematologic malignancies. Nearly 50% of allo-HCT patients will develop acute GVHD, characterized by an exacerbated inflammatory response and organ toxicity, the skin being the most commonly involved organ. 

 

Hepcidin, the key regulatory hormone of iron homeostasis, is primarily produced by hepatocytes, but many cells and tissues express this hormone in pathological conditions. We have generated a new mouse model overexpressing hepcidin in keratinocytes and demonstrated a marked phenotype including, alopecia and epidermis thickening with local iron retention, together with a dramatic increase of IL-1β, TNF-α, CCL2, CXCL16 and CCL8 expression, and a massive immune cell infiltration, especially T lymphocytes, in the skin. Strikingly, this phenotype resembles some characteristics of patients suffering from GVHD, particularly the early events of the disease. Importantly, our data in skin biopsies of GVHD patients revealed for the first time an increase of hepcidin expression.  

 

Interestingly, in control mice, performing only the irradiation conditioning regimen (prior to transplantation) is sufficient to induce skin hepcidin expression with concomitant iron accumulation, questioning the role of iron in the early steps of GVHD, in particular with regards to T cell activation.

There is no doubt that studying the impact of iron and hepcidin in GVHD, both in murine models and in humans, may have potential for novel preventive/therapeutic drugs that are urgently needed to prevent/cure GVHD.