Heme catabolism and heme oxygenase-1-expressing myeloid cells in pathophysiology

Abstract

Although the pathological significance of myeloid cell heterogeneity is still poorly understood, new evidence indicates that distinct macrophage subsets are characterized by specific metabolic programs that influence disease onset and progression. Within this scenario, distinct subsets of macrophages, endowed with high rates of heme catabolism by the stress-responsive enzyme heme oxygenase-1 (HO-1), play critical roles in physiologic and pathological conditions. Of relevance, the substrates of HO-1 activity are the heme groups that derive from cellular catabolism and are converted into carbon monoxide (CO), biliverdin and Fe2+, which together elicit anti-apoptotic, anti-inflammatory activities and control oxidative damage. While high levels of expression of HO-1 enzyme by specialized macrophage populations (erythrophagocytes) guarantee the physiological disposal of senescent red blood cells (i.e. erythrocateresis), the action of HO-1 takes on pathological significance in various diseases, and abnormal CO metabolism has been observed in cancer, hematological diseases, hypertension, heart failure, inflammation, sepsis, neurodegeneration. Modulation of heme catabolism and CO production is therefore a feasible therapeutic opportunity in various diseases. In this review we discuss the role of HO-1 in different pathological contexts (i.e. cancer, infections, cardiovascular, immune-mediated and neurodegenerative diseases) and highlight new therapeutic perspectives on the modulation of the enzymatic activity of HO-1.

Keywords: HO-1; immunemetabolism; immunosuppression; innate immunity; myeloid cells.

Figure 1

The heme oxygenase enzyme reaction and products. Heme is enzymatically degraded into biliverdin (BV), carbon monoxide (CO) and Iron. Biliverdin (BV) is subsequently transformed into bilirubin (BR) by biliverdin reductase (BVR). Iron can be bound by Ferritin, a protein able to store iron. The heme molecule provides a variety of fundamental biological functions as forming of various apo-heme proteins like hemoglobin, nitric oxide synthase and cytochromes. The HO-1-derived product CO could exert anti-inflammatory, anti-proliferation, anti-apoptosis, and vasodilation effects in immune system. BR can perform a crucial role in anti-inflammation, anti-proliferation, anti-apoptosis, anti-oxidation, and free radical scavenger. Moreover, iron-induced ferritin could play a cytoprotective, anti-oxidative and iron storage effect. A list of abbreviations and acronyms used in the manuscript has been included in Table 1 .

Figure 2

Distinct roles of myeloid HO-1⁺ cells in pathology. Multifaced functions of HO-1⁺ myeloid cells during the onset and progression of several diseases, depending on the pathological contest. MI, myocardial infarction; MS, multiple sclerosis; PD, Parkinson’s Disease; AD, Alzheimer Disease; RA, rheumatoid arthritis; Lysteria M, Lysteria Monocytogenes; Salmonella T, Salmonella Thyphimurium; IBD, Inflammatory Bowel Diseases; LD, Lung Diseases.

Figure 3

Signaling pathways leading to myeloid HO-1 induction in pathology. The scheme shows potential interrelationships between signaling events promoting transcriptional activation of HO-1 in myeloid cells in different pathophysiological conditions, such as tumors, cardiovascular diseases (ischemic conditions, MI, atherosclerosis, and hypertension) neurodegenerative disorders (AD, PD), immune-mediated diseases (SLE, MS and RA) bacterial and viral infections (Salmonella thyphimurium, Listeria monocytogenes, HIV and SARS-CoV-2). Several noxious stimuli (i.e. ROS, hypoxia, oxidative stress, hemorrhage/heme, free iron) and inflammatory mediators (i.e. IL-6, VEGF, CSF-1, C3a, EGF, HIF-1a) as well as hemoglobin/haptoglobin through CD163 receptor are known inducers of transcription of HO-1, primarily promoting KEAP-1/Nrf2 nuclear translocation and nuclear export of the transcriptional repressor BACH1. Activation of MAPK/PI3K/AKT, AP-1 and NF-κB by environmental stresses and cytokines has also been implicated in HO-1 activation. HO-1, heme oxygenase-1; MI, myocardial infarction, AD, Alzheimer’s disease; PD, Parkinson’s disease; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis; MS, multiple sclerosis; CSF-1, colony stimulating factor 1; MAPK, mitogen-activated protein kinase; Nrf2, NF-E2 related factor-2; HIF-1a, hypoxia inducible factor; AP-1, activator protein-1; BACH1, HO-1 transcriptional repressor; ROS, reactive oxygen species; PI3K, phosphatidylinositol 3-kinase. Created by biorender.com.