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Review
. 2014 May 27:5:115.
doi: 10.3389/fphar.2014.00115. eCollection 2014.

Heme on innate immunity and inflammation

Fabianno F Dutra  1 , Marcelo T Bozza  1
Affiliations
Review

Heme on innate immunity and inflammation

Fabianno F Dutra et al. Front Pharmacol. .

Abstract

Heme is an essential molecule expressed ubiquitously all through our tissues. Heme plays major functions in cellular physiology and metabolism as the prosthetic group of diverse proteins. Once released from cells and from hemeproteins free heme causes oxidative damage and inflammation, thus acting as a prototypic damage-associated molecular pattern. In this context, free heme is a critical component of the pathological process of sterile and infectious hemolytic conditions including malaria, hemolytic anemias, ischemia-reperfusion, and hemorrhage. The plasma scavenger proteins hemopexin and albumin reduce heme toxicity and are responsible for transporting free heme to intracellular compartments where it is catabolized by heme-oxygenase enzymes. Upon hemolysis or severe cellular damage the serum capacity to scavenge heme may saturate and increase free heme to sufficient amounts to cause tissue damage in various organs. The mechanism by which heme causes reactive oxygen generation, activation of cells of the innate immune system and cell death are not fully understood. Although heme can directly promote lipid peroxidation by its iron atom, heme can also induce reactive oxygen species generation and production of inflammatory mediators through the activation of selective signaling pathways. Heme activates innate immune cells such as macrophages and neutrophils through activation of innate immune receptors. The importance of these events has been demonstrated in infectious and non-infectious diseases models. In this review, we will discuss the mechanisms behind heme-induced cytotoxicity and inflammation and the consequences of these events on different tissues and diseases.

Keywords: ROS; cytotoxicity; heme; hemolysis; inflammation; innate immunity; iron; programed cell death.

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Figures

FIGURE 1
FIGURE 1
Heme activates TLR4 in macrophages. The TLR4 activates two distinct pathways: MyD88 and TRIF. In macrophages, heme induces a biased MyD88 activation and the secretion of the pro-inflammatory cytokines TNF and KC. TLR4 activation leads to MAPKs and NFκB activation, which are necessary to TNF secretion. Heme induces ROS generation independently of TLR4. However, ROS is necessary to induce TNF secretion and MAPK activation. Thus, TLR4 activation and ROS generation seem to be complementary and both are required for MAPKs and IκB degradation. It will be important to determinate the source of ROS and the mechanisms triggering heme-induced ROS generation. The mitochondria and the NADPH oxidase complexes seem to be involved. mROS scavenger (Mito-TEMPO) and NADPH oxidases inhibitors (apocynin and DPI) block TNF production induced by heme.
FIGURE 2
FIGURE 2
Heme induces RIP1/RIP3-dependent programed cell death. Heme triggers two distinct but integrated pathways to promote necroptosis. Heme induces ROS generation independently of TLR4. ROS sensitizes macrophages to TNFR-induced cell death. Heme-induced TLR4 activation leads to MAPKs activation and TNF production. While JNK increases ROS generation, TNF induces RIP1–RIP3 necrosome which triggers necroptosis. The mitochondria and the NADPH oxidase complexes seem to be involved. mROS scavenger (Mito-TEMPO) and NADPH oxidases inhibitors (apocynin and DPI) block heme-induced necroptosis. Necroptosis only develops when caspases are inhibited. However, it is not known if heme requires caspase inhibition to induce necroptosis. Moreover, HO-1 has a protective effect during heme-induced necroptosis.
FIGURE 3
FIGURE 3
Heme activates Syk and amplifies cytokine production induced by PAMPs. Heme induces Syk phosphorylation in macrophages. The Syk pathway is essential for heme-induced ROS production. Heme-induced ROS generation increases MAPKs and NFκB activation and consequently, cytokine production. Heme amplifies cytokines induced by cell surface receptors (TLR2, TLR4, TLR5), endosome receptors (TLR3, TLR9), and cytosolic receptors (NOD1 and NOD2). Moreover, heme amplifies MyD88- (TNF and IL-6) and TRIF-dependent (IP-10) cytokines. The mechanism by which heme triggers Syk activation is not known. However, there are two possibilities. Heme could trigger Syk activation through an unknown surface receptor or through interaction with lipid rafts. The source of ROS controlled by Syk is not known but because PKC, NOX, and mitochondria inhibitors blocks the synergism between heme and PAMPs it is possible to consider that Syk controls ROS generation by NOX and mitochondria. Although NOX2 is the principal NADPH oxidase complex in phagocytes we cannot exclude the possibility that other NOX might be involved.
FIGURE 4
FIGURE 4
Heme induces vascular inflammation in hemolytic diseases. During intravascular hemolysis the serum proteins responsible for removing heme get saturated and heme can exert its inflammatory effects. (1) Hemolysis can happen due to ischemia/reperfusion, SCD or β-thalassemia. While in SCD, Hb polymerization alters erythrocytes physically, in β-thalassemia the accumulation of α-globin aggregates inside the erythrocytes. In both cases, the erythrocytes became more susceptible to hemolysis. Hemolysis increases the concentration of Hb which, under oxidative stress, releases free heme. (2) Heme activates neutrophils and endothelial cells, by ROS generation. In both cells, heme induces the expression of complementary adhesion molecules. In endothelial cells, heme induces TLR4-dependent degranulation of Weibel–Palade bodies and P-selectins and VWF release. The VWF is prothrombotic and can increase the adhesion of erythrocytes to the endothelium. Heme also induces the expression of the adhesion molecules ICAM-1, VCAM-1, and E-selectins. Neutrophils stimulated by heme and TNF releases NETs. (3) These events lead to the adhesion of neutrophils to endothelial cells. The activated endothelium now expresses molecules that can interact with surface molecules localized in erythrocytes. Also, erythrocytes express molecules that can interact with platelets. Together, these events lead to vaso-occlusion. (4) Depending on the extension of the vaso-occlusion, some tissues may experience hypoxia and damage. Vaso-occlusion of the lung microvasculature may result in the development of the ACS through the infarction of the lung parenchyma. Heme-induced TLR4 activation in endothelial cells and NETs release contribute to the ACS.
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References

    1. Adisa O. A., Hu Y., Ghosh S., Aryee D., Osunkwo I., Ofori-Acquah S. F. (2013). Association between plasma free haem and incidence of vaso-occlusive episodes and acute chest syndrome in children with sickle cell disease. Br. J. Haematol. 162 702–705 10.1111/bjh.12445 - DOI - PMC - PubMed
    1. Aft R. L., Mueller G. C. (1983). Hemin-mediated DNA strand scission. J. Biol. Chem. 258 12069–12072 - PubMed
    1. Aft R. L., Mueller G. C. (1984). Hemin-mediated oxidative degradation of proteins. J. Biol. Chem. 259 301–305 - PubMed
    1. Arosio P., Ingrassia R., Cavadini P. (2009). Ferritins: a family of molecules for iron storage, antioxidation and more. Biochim. Biophys. Acta 1790 589–599 10.1016/j.bbagen.2008.09.004 - DOI - PubMed
    1. Arroyo L. H., Lee R. T. (1999). Mechanisms of plaque rupture: mechanical and biologic interactions. Cardiovasc. Res. 41 369–375 10.1016/S0008-6363(98)00308-3 - DOI - PubMed