Red alert: labile heme is an alarmin

Abstract

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.

Protein aggregation as a cellular response to oxidative stress induced by heme and iron

“…Indeed, in several experimental models, the cytotoxicity attributed to ), no longer available to catalyze the production of free radicals via a Fenton reaction (7,8). Consistently, the absence of FtH resulted in higher levels of p62 expression on treatment with Fe2 + , but not on treatment with Fe3…”

“…However, when released into the extracellular milieu, heme can exert several deleterious effects, resulting in damage to lipids (4), proteins (5), and DNA (6). In pathological conditions that result in hemolysis, rhabdomyolysis, or extensive cell damage, large amounts of hemeproteins are released, and under oxidative conditions, the heme moiety is released, further increasing oxidation and cellular stress (7,8). Recently, it was shown that heme can induce the generation of reactive oxygen species (ROS) through the activation of NADPH oxidase (9) or by the mitochondria (10), and that blocking these pro-oxidant effects protects the host from cell damage and tissue injury.…”

Intravascular hemolysis and the pathophysiology of sickle cell disease

“…In humans, impaired NO signaling, directly measured via venous occlusion strain-gauge plethysmography, correlates with high levels of plasma hemoglobin and LDH (16). This was recently confirmed in a study of SCD patients correlating high plasma hemoglobin levels appreciated as an additional important mediator of inflammation and vascular injury (102,103). In sickle cell mice, free heme drives inflammation, vaso-occlusion, and coagulation that are blocked by the heme scavenger hemopexin (104)(105)(106)(107)(108)(109).…”

Macrophages and Iron Metabolism

“…Due to the high intracellular heme content of RBCs and muscle cells, detection of extracellular heme by macrophages probably reports on RBC and/or muscle cell damage, associated with hemolysis or rhabdomyolysis, respectively (Soares and Bozza, 2016). When released from damaged RBC or muscle cells, extracellular hemoglobin and myoglobin are prone to oxidation, releasing their heme prosthetic groups.…”