Heme: The Lord of the Iron Ring

Abstract

Heme is an iron-protoporphyrin complex with an essential physiologic function for all cells, especially for those in which heme is a key prosthetic group of proteins such as hemoglobin, myoglobin, and cytochromes of the mitochondria. However, it is also known that heme can participate in pro-oxidant and pro-inflammatory responses, leading to cytotoxicity in various tissues and organs such as the kidney, brain, heart, liver, and in immune cells. Indeed, heme, released as a result of tissue damage, can stimulate local and remote inflammatory reactions. These can initiate innate immune responses that, if left uncontrolled, can compound primary injuries and promote organ failure. In contrast, a cadre of heme receptors are arrayed on the plasma membrane that is designed either for heme import into the cell, or for the purpose of activating specific signaling pathways. Thus, free heme can serve either as a deleterious molecule, or one that can traffic and initiate highly specific cellular responses that are teleologically important for survival. Herein, we review heme metabolism and signaling pathways, including heme synthesis, degradation, and scavenging. We will focus on trauma and inflammatory diseases, including traumatic brain injury, trauma-related sepsis, cancer, and cardiovascular diseases where current work suggests that heme may be most important.

Keywords: cancer; cardiovascular; heme; heme-oxygenase; sepsis; traumatic brain injury.

Figure 1

Heme “the lord of the iron ring” toxicity after large amounts are released into the bloodstream. Traumatic injury, infection, and disturbances in the cardiovascular system have all independently been shown to be influenced by heme release and metabolism as it relates to cell survival and tissue repair. Heme has toxic properties in each scenario due in large part to the catalytic active iron atom it coordinates, but heme also acts as a ligand for Toll-like receptors (TLR). After traumatic injury, high concentrations of heme contribute to an inflammatory response with additional heme-dependent tissue injury. In sepsis, the accumulation of heme as a result of tissue injury induces a prototypical cytokine storm, oxidant radical generation, transcription factor mobilization, and resulting stress response gene expression. However, tissue injury initiates a sequence of events that also leads to immunosuppression that increases the host’s risk of infection at barrier sites such as the lung. Disturbances in the cardiovascular system also promote the release of excessive heme, resulting in vascular dysfunction through the increased expression of adhesion molecules, endothelial activation, immune cell recruitment and platelet aggregation, as well as the consumption of nitric oxide that leads to vasoconstriction. Heme-injured myocytes exhibit morphological changes and oxidative enzyme loss, leading to a reduction in the contractile function of the heart. These effects highlight the importance of the tight regulation of heme levels in the body so as to prevent its harmful consequences on cell and tissue function.

Figure 2

The dual role of heme in the tumor microenvironment. The modulation of ferritin and HO-1 expression in the setting of heme overload, such as the ingestion of red meat or acute tissue injury, induces DNA damage and increases the risk for colorectal cancer (CRC). In addition to the extracellular heme released by blood vessels irrigating the tumor microenvironment (TME), tumor cells can also increase heme biosynthesis while improving their mitochondrial bioenergetic response, including oxidative phosphorylation (OXPHOS), that augment survivability and proliferation. The increased HO-1 expression in tumor-infiltrating macrophages (TAMs) can promote tumor cell migration and metastasis. Conversely, TAMs can also switch to an antitumoral M1 phenotype in response to heme exposure in the TME. Moreover, heme metabolism by HO-1 in TAMs can induce tumor cell death in part by increasing Fe²⁺-mediated ferroptosis. Carbon monoxide (CO) can also impart potent anti-proliferative effects that may contribute to iron-mediated cell death. Thick arrows up indicate an increase, while thick arrows down indicate a decrease.