Abstract
Heme is one of the most abundant molecules in the body acting as the functional core of hemoglobin/myoglobin involved in the O2/CO2 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.
Highlights
Many human diseases are associated with immune dysfunctions affecting the host ability to control inflammation
HO-1 activity may help to mitigate DNA damage, gene mutation and carcinogenesis resulting from excessive reactive oxygen species (ROS) levels; we have previously showed that HO-1/carbon monoxide (CO) facilitate DNA damage repair via ATM-γH2AX mechanism in normal cells [129]
We showed that HO-1 in tumor-associated macrophages (TAMs) is critical for regulating epithelial-mesenchymal transition (EMT) and metastatic outgrowth in prostate cancer [136]
Summary
Many human diseases are associated with immune dysfunctions affecting the host ability to control inflammation. The role of BLVR-A in inflammation has been primarily described in myeloid cells including macrophages, where this enzyme is expressed as a cell surface protein [47] Both macrophage BLVR-A expression and phosphorylation are increased upon LPS-treatment which leads to anti-inflammatory responses by stimulating PI3K-Akt-driven IL-10 production [47]. BR binds directly to PPARα and elevated total serum BR levels have been reported to negatively correlate with onset of the disease in NAFLD and NASH patients [110,111,112,113] These data indicate a major role of BLVR-A in hepatic lipid metabolism and associated inflammation, supporting an additional role for BR as a protective factor against the progression and development of chronic liver disease. This suggests that targeting BR metabolism and/or BLVR enzymatic activity could have important consequences in the tissue microenvironment and could be a potential therapeutic approach for metabolic, cardiovascular, oncogenic and neurological disorders as well
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