Red alert: labile heme is an alarmin

doi:10.1016/j.coi.2015.11.006

Current Opinion in Immunology

Volume 38, February 2016, Pages 94-100

https://doi.org/10.1016/j.coi.2015.11.006 Get rights and content

Highlights

•
Damaged cells release hemoproteins.
•
Hemoproteins can release their prosthetic heme groups.
•
Labile heme is sensed by pattern recognition receptors.
•
Labile heme is an alarmin.

Alarmins are a heterogeneous group of endogenous molecules that signal cellular damage when sensed extracellularly. Heme is an endogenous molecule that acts as a prosthetic group of hemoproteins, such as hemoglobin and myoglobin. When released from damaged red blood cells or muscle cells, oxidized hemoglobin and myoglobin release their prosthetic heme groups, respectively. This generates labile heme, which is sensed by pattern recognition receptors (PRR) expressed by innate immune cells and possibly regulatory T cells (T_REG). The ensuing adaptive response, which alerts for the occurrence of red blood cell or muscle cell damage, regulates the pathologic outcome of hemolysis or rhabdomyolysis, respectively. In conclusion, we propose that labile heme is an alarmin.

Introduction

This opinion article builds up on several assumptions. First, that all living organisms can sense events that alert for a possible disruption of homeostasis [1^••]. Second, that such sensors trigger adaptive responses that contribute to maintain or restore homeostasis [2•, 3•]. Third, that host/microbe interactions often lead to disruption of homeostasis. Fourth, that sensing microorganisms alert for a possible disruption of homeostasis. Based on these general principles pattern recognition receptors (PRRs) where proposed to act as bona fide homeostatic sensors [1^••].

Engagement of PRR by pathogenic microorganisms is essential to elicit adaptive immune responses conferring resistance to infections [4, 5]. In addition, PRR also play a pivotal role in maintaining steady state interactions with commensal microorganisms [6]. Moreover, PRR can sense endogenous molecules released from damaged cells [7], presumably reporting on cellular damage and on possible disruption of homeostasis. The endogenous molecules recognized by PRR were originally designated as danger associated molecular patters, based on the assumption that these are sensed when released from damaged cells [8, 9]. The term alarmin is also used to refer to any endogenous molecule that signals cellular damage [10]. We shall argue herein that labile heme is a prototypical alarmin.

Section snippets

Labile heme

Heme is an evolutionarily conserved molecular structure composed of a tetrapyrrole ring surrounding a single iron (Fe) atom (Figure 1). Heme acts essentially as a prosthetic group in a number of hemoproteins. These include hemoglobin (Hb) and myoglobin (Mb), which contain the largest pool of bioavailable heme in mammals [11]. When damaged, red blood cells and muscle cells release Hb and Mb, respectively. Extracellular Hb and Mb are readily oxidized, via a process catalyzed by the transition of

Sensing labile heme

The finding that when exposed in vitro to labile heme Mø secrete tumor necrosis factor (TNF) via a mechanism dependent on the expression of TLR4 and its adaptor signaling molecule MyD88, revealed that labile heme is sensed by PRR [27]. More recently labile heme was shown to induce, again via a TLR4-dependent mechanism, the expression of molecules associated with endothelial cell activation, an effect that presumably contributes to the pathogenesis of sickle cell disease [20, 22•]. Labile heme

Labile heme is an alarmin

Given the extraordinarily high intracellular heme content of red blood cells and muscle cells, as compared to any other cell type, sensing extracellular labile heme probably signals red blood cell and/or muscle cell damage, associated with hemolysis or rhabdomyolysis, respectively (Figure 2). In keeping with this notion, labile heme triggers cell autonomous and systemic adaptive responses that mitigate the pathogenic outcomes of hemolysis [25, 29] and rhabdomyolysis [30]. This protective effect

Labile heme as an amplifier of inflammation

Systemic infections are often associated with varying levels of hemolysis and in some cases with rhabdomyolysis as well. The extracellular Hb generated through hemolysis exerts anti-microbial effects, via the peroxidase activity of its prosthetic heme b groups, which uses hydrogen peroxide (H₂O₂) to oxidize molecules in microbes [38, 39]. Moreover, binding of extracellular Hb to bacterial lipopolysaccharide (LPS) [40], alters the tertiary structure of Hb [39, 41], enhancing its peroxidase and

Labile heme as a cytotoxic agonist

Labile heme is not only cytotoxic to pathogens but also to host cells [44, 46, 47]. The very same structural features that render heme b a versatile redox active molecule when contained in the heme pockets of hemoproteins, drive its pathologic effects when released from those hemoproteins. The general principle being that the amphipathic nature of the tetrapyrrole ring of heme favors its interaction with nonpolar molecules such as phospholipids in cellular membranes. If not countered promptly,

Conclusion

Labile heme is a prototypical alarmin. In contrast to other alarmins however, labile heme is endowed with cytotoxicity, potentially amplifying the release of other alarmins from damaged cells. Presumably this explains the broad protective effects exerted by the adaptive response triggered in response to this alarmin, which converges at the level of heme catabolism by HO-1 and acts in a protective manner against a variety of immune mediated inflammatory diseases.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

The authors thank Luis Ferreira Moita (Instituto Gulbenkian de Ciência) for critical review of the manuscript and Zélia Gouveia for producing the heme structures in Figure 1. MPS is supported by Fundação Calouste Gulbenkian and by grants from the Fundação para a Ciência e Tecnologia (PTDC/SAU TOX/116627/2010, HMSP-ICT/0022/2010, RECI/IMI-IMU/0038/2012) and by the European Community 7th Framework Grant ERC-2011-AdG. 294709-DAMAGECONTROL. MTB is supported by Fundação de Amparo a Pesquisa do

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Red alert: labile heme is an alarmin

Highlights

Introduction

Section snippets

Labile heme

Sensing labile heme

Labile heme is an alarmin

Labile heme as an amplifier of inflammation

Labile heme as a cytotoxic agonist

Conclusion

References and recommended reading

Acknowledgements

Cell

Mol Cell

Nature

Ann Rev Immunol

Blood

J Mol Med

Nat Med

Cell

Trends Mol Med

Nat Immunol

DNA Cell Biol

Infect Immun

Science

Blood

Cell Host Microbe

Science

Histol Histopathol

Cell

Cell

J Immunol

Free Radic Biol Med

Blood

J Immunol

J Biol Chem

Tissue damage control in disease tolerance

Trends Immunol

Approaching the asymptote?. Evolution and revolution in immunology

Cold Spring Harb Symp Quant Biol

Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis

Cell

Origin and physiological roles of inflammation

Nature

Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses

Nat Rev Immunol

DAMPs, PAMPs and alarmins: all we need to know about danger

J Leukoc Biol

The Iron age of host–microbe interactions

EMBO Rep

Endothelial-cell heme uptake from heme proteins: induction of sensitization and desensitization to oxidant damage

Proc Natl Acad Sci USA

Mechanisms of cell protection by heme oxygenase-1

Annu Rev Pharmacol Toxicol

Coupling heme and iron metabolism via ferritin H chain

Antioxid Redox Signal