Heme Cytotoxicity and the Pathogenesis of Immune-Mediated Inflammatory Diseases

Rasmus Larsen,Zélia Gouveia,Raffaella Gozzelino,Miguel P Soares

doi:10.3389/fphar.2012.00077

Abstract

Heme, iron (Fe) protoporphyrin IX, functions as a prosthetic group in a range of hemoproteins essential to support life under aerobic conditions. The Fe contained within the prosthetic heme groups of these hemoproteins can catalyze the production of reactive oxygen species. Presumably for this reason, heme must be sequestered within those hemoproteins, thereby shielding the reactivity of its Fe-heme. However, under pathologic conditions associated with oxidative stress, some hemoproteins can release their prosthetic heme groups. While this heme is not necessarily damaging per se, it becomes highly cytotoxic in the presence of a range of inflammatory mediators such as tumor necrosis factor. This can lead to tissue damage and, as such, exacerbate the pathologic outcome of several immune-mediated inflammatory conditions. Presumably, targeting “free heme” may be used as a therapeutic intervention against these diseases.

Highlights

Heme, iron (Fe) protoporphyrin IX, functions as a prosthetic group in a range of hemoproteins essential to support life under aerobic conditions
When present in the heterozygous form, the Hb β6Glu > Val sickle mutation is not pathogenic, conferring instead a net survival advantage to human population living in endemic areas of malaria (Williams et al, 2005b). This protective effect acts via a mechanism involving the accumulation of low levels of free heme in plasma that induce the expression of HO1 via activation of the transcription factor NF-E2-related factor 2 (Nrf2; Ferreira et al, 2011)
Expression of HO-1 exerts strong protective effects against ischemia–reperfusion injury (IRI), via a mechanism that is not clear but is likely to involve the catabolism of deleterious free heme, which is in keeping with the notion that hemolysis might act as an inherent component of the pathogenesis of IRI

Summary

Introduction

Iron (Fe) protoporphyrin IX, functions as a prosthetic group in a range of hemoproteins essential to support life under aerobic conditions. This mechanism should contribute to prevent the pathogenesis and/or progression of other immune-mediated inflammatory diseases associated with heme release from hemoproteins (reviewed in Ferreira et al, 2008; Gozzelino et al, 2010).

Results

Conclusion