Heme-Derived Metabolic Signals Dictate Immune Responses

Abstract

Heme is one of the most abundant molecules in the body acting as the functional core of hemoglobin/myoglobin involved in the O 2 /CO 2 carrying in the blood and tissues, redox enzymes and cytochromes in mitochondria. However, free heme is toxic and therefore its removal is a significant priority for the host. Heme is a well-established danger-associated molecular pattern (DAMP), which binds to toll-like receptor 4 (TLR4) to induce immune responses. Heme-derived metabolites including the bile pigments, biliverdin (BV) and bilirubin (BR), were first identified as toxic drivers of neonatal jaundice in 1800 but have only recently been appreciated as endogenous drivers of multiple signaling pathways involved in protection from oxidative stress and regulators of immune responses. The tissue concentration of heme, BV and BR is tightly controlled. Heme oxygenase-1 (HO-1, encoded by HMOX1) produces BV by heme degradation, while biliverdin reductase-A (BLVR-A) generates BR by the subsequent conversion of BV. BLVR-A is a fascinating protein that possesses a classical protein kinase domain, which is activated in response to BV binding to its enzymatic site and initiates the downstream mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. This links BLVR-A activity to cell growth and survival pathways. BLVR-A also contains a bZip DNA binding domain and a nuclear export sequence (NES) and acts as a transcription factor to regulate the expression of immune modulatory genes. Here we will discuss the role of heme-related immune response and the potential for targeting the heme system for therapies directed toward hepatitis and cancer.

BVR-A Deficiency Leads to Autophagy Impairment through the Dysregulation of AMPK/mTOR Axis in the Brain—Implications for Neurodegeneration

“…During its catabolism, heme is initially converted by heme oxygenase (HO) to biliverdin, which is then reduced to bilirubin through the action of BVR [1,2]. Two different isoforms of BVR were detected in humans and named BVR-A and BVR-B [3]. Although both isozymes catalyze the reduction of biliverdin, BVR-A selectively reduces biliverdin IXα to bilirubin IXα, one of the strongest endogenous antioxidants [3,4].…”

“…Two different isoforms of BVR were detected in humans and named BVR-A and BVR-B [3]. Although both isozymes catalyze the reduction of biliverdin, BVR-A selectively reduces biliverdin IXα to bilirubin IXα, one of the strongest endogenous antioxidants [3,4]. For that reason, BVR-A has been studied for a long time as an antioxidant enzyme capable of counteracting oxidative stress-induced alterations [1,2,5].…”

“…Interestingly, several sequence motifs within the BVR-A structure were identified as possible protein-protein interaction sites [11]. BVR-A was shown to be a Ser/Thr/Tyr kinase able to regulate a number of pathways involved in cell growth, differentiation and survival [1,3,12]. In particular, BVR-A was identified as a novel regulator of the insulin/IGF1 signaling in vitro [13][14][15] and recent studies showing that loss of BVR-A impairs insulin signaling activation and cell metabolism also in vivo support this hypothesis [16][17][18][19].…”

“…BVR-A can translocate to the nucleus acting as a bZIP-type transcription factor, controlling the expression of genes involved in stress-responses [ 6 , 7 , 8 , 9 , 10 ]. Furthermore, BVR-A was reported to play a pivotal role in regulating inflammatory responses [ 3 , 10 ]. Interestingly, several sequence motifs within the BVR-A structure were identified as possible protein–protein interaction sites [ 11 ].…”

Heme Oxygenase 1 (HO-1) as an Inhibitor of Trafficking of Normal and Malignant Hematopoietic Stem Cells – Clinical and Translational Implications

“…Heme oxygenase is represented by two isozymes, of which heme oxygenase 2 is constitutively expressed, and heme oxygenase 1 (HO-1) is induced in response to its substrate heme and other mediators [1]. This inducible stress-response enzyme not only catalyzes the degradation of heme (e.g., released as a component of hemoglobin from erythrocytes) but also has important pleiotropic functions in various physiological and pathophysiological states associated with cellular stress, infections, and tissue/organ damage [1][2][3][4][5]. Recent studies have implicated HO-1 as an important regulator of mitochondrial biogenesis and mitochondrial function, as well as lipid and polyamines metabolism [6].…”