Targeting Iron/Heme in Infectious Disease

Abstract

Inflammation and immunity can be associated with varying degrees of hemolysis and as such with heme release from cell-free hemoglobin (Hb), i.e. free heme. Accumulation of free heme in plasma can lead, eventually, to tissue iron (Fe) overload, oxidative stress, and tissue damage. Presumably, these deleterious effects contribute critically to the pathogenesis of systemic infections, as illustrated for severe sepsis (1) as well as for severe forms of malaria (2). Free heme sensitizes parenchyma cells to undergo programmed cell death in response to pro-inflammatory agonists (1). This cytotoxic effect is driven by the intracellular accumulation of free radicals, which sustain the activation of the c-Jun N-terminal Kinase (JNK) signaling transduction pathway. While heme catabolism by heme oxygenase1 (HO-1) prevents heme driven programmed cell death, this cytoprotective effect requires the co-expression of ferritin H chain (FTH), which controls the pro-oxidant labile Fe released from the protoporphyrin IX ring of heme (3). The antioxidant effect of FTH restrains JNK activation, while JNK activation inhibits FTH expression, a crosstalk that controls metabolic adaptation to cellular Fe overload during systemic infections (4).1. Larsen, R. et al., Sci Transl Med 2 (51), 51ra71 (2010).2. Pamplona, A. et al., Nat Med 13 (6), 703 (2007); Ferreira, A. et al., J Mol Med 86 (10), 1097 (2008); Ferreira, A. et al., Cell 145 (April 29), 398 (2011).3. Gozzelino, R. et al., Cell Host Microbe 12 (5), 693 (2012)4.Medzhitov, R, Schneider, DS, and Soares. Science 335, 936 (2012). Disclosures:No relevant conflicts of interest to declare.