Heme Oxygenase 1 for Inflammatory Disease/Viral Clearance: Comparison
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Please note this is a comparison between Version 2 by Yvaine Wei and Version 1 by Geraldine Gueron.

Heme oxygenase 1 (HO-1), the rate-limiting enzyme in heme degradation, is involved in the maintenance of cellular homeostasis, exerting a cytoprotective role by its antioxidative and anti-inflammatory functions. HO-1 and its end products, biliverdin (BV), carbon monoxide (CO) and free iron (Fe2+), confer cytoprotection against inflammatory and oxidative injury. Additionally, HO-1 exerts antiviral properties against a diverse range of viral infections by interfering with replication or activating the interferon (IFN) pathway. Severe cases of coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are characterized by systemic hyperinflammation, which, in some cases, leads to severe or fatal symptoms as a consequence of respiratory failure, lung and heart damage, kidney failure, and nervous system complications. Here we summarize the current research on the protective role of HO-1 in inflammatory diseases and against a wide range of viral infections, positioning HO-1 as an attractive target to ameliorate clinical manifestations during COVID-19.

  • heme oxygenase 1
  • COVID-19
  • influenza A virus
  • respiratory syncytial virus
  • human immunodeficiency virus
  • Ebola virus
  • Dengue virus
  • Zika virus
  • SARS-CoV-2

1. Introduction

The treatment goal in COVID-19 patients is to prevent or to decrease the strong virus induced inflammatory stimuli associated with a wide spectrum of poor prognosis clinical manifestations [1]. HO-1 is a microsomal enzyme with a primary antioxidant and anti-inflammatory role involved in heme degradation, generating CO, BV, and Fe2+ [2]. Hence, HO-1 induction is a useful approach for inflammatory diseases treatment [3][4][5][6]. Additionally, HO-1 displays antiviral properties against a wide range of viruses [7]. Hemin, a previously Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved drug for acute intermittent porphyria treatment [8][9], is a well known inducer of HO-1 that increases its plasma concentration in humans. Thus, hemin rises as a promising drug candidate against the replication of different viruses, including SARS-CoV-2.

2. Cytokine Storm and Inflammation

Inflammation involves defense mechanisms against infection or injury. It is responsible for activating both innate and adaptive immune responses [10][11]. During infections, innate cells recognize pathogen associated molecular patterns from the invading agent. In the case of inflammation triggered by tissue damage, trauma or ischemia, innate cells recognize host specific molecules that are released during cell injury or necrotic death, defined as damage associated molecular patterns, such as nucleic acids and adenosine triphosphate [10]. During the early stages of inflammation, innate immune cells and endothelial cells (EC) release a diverse set of cytokines and recruit other immune cells to the site of infection or inflammation. Proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-1β [12][13], are also released and trigger the activation of inflammatory pathways, including the mitogen activated protein kinase (MAPK), nuclear factor kappa-B (NF-κB), and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways [11]. Some pathogenic viruses (i.e., highly virulent subtypes of influenza) and bacteria (i.e., Francisella tularensis) can induce the acute dysregulated production of inflammatory cytokines, known as “cytokine storm” or hypercytokinemia [14]. The hypercytokinemia and exacerbated secondary events, such as coagulation, eventually result in widespread necrosis, organ failure and death [10][15]. Once SARS-CoV-2 infects target cells, innate immune cells are recruited to the infection site, where they release cytokines and initiate the activation cascade of adaptive B and T cell immune responses [16]. In most cases, the immune system is able to eliminate virus infected cells and resolve the immune response. However, in some patients, this process is dysfunctional, impairing the effective clearance of infected cells, and causing severe damage to the host [17].

3. The Lead Role of Interferons upon Viral Infection

During viral infections, pattern recognition receptors are stimulated to produce IFN by the innate immune cells. IFNs are crucial for the induction of an antiviral state via autocrine and paracrine signaling. There are three types of IFNs: type I, type II and type III. Type I (IFNα, IFNβ, IFNω, IFNτ, IFNε) and Type III (IFNλ1, IFNλ2/3, IFNλ4) share similar dynamics after binding to its receptor, as cross-phosphorylation between JAK1 and tyrosine kinase 2 (TYK2) occurs [18]. Subsequently, a docking site for STAT1 is exposed, STAT1 is phosphorylated, translocates to the nucleus, and induces the transcription of interferon stimulated genes (ISGs). The IFNs biological effects are wide, including immuno-regulation, antiviral, anti-angiogenic, and pro-apoptotic functions [19]. However, many pathogens have evolved to elude the action mechanisms of these powerful cytokines [20][21][22].

4. Understanding the Protective Role of Heme Oxygenase 1

Heme oxygenases (HO) are metabolic enzymes that partake in the degradation of the heme group [2]. To date, three isoforms of this protein have been found: HO-1, which can be induced by external factors (such as hypoxia, oxidative stress, heat shock, reactive oxygen species (ROS), among others) [23]; HO-2, a constitutively expressed isoform; and HO-3, a non-functional isoform in humans [24]. In particular, HO-1, encoded by the HMOX1 gene, is involved in the maintenance of cellular homeostasis, exerting a cytoprotective role by its anti-inflammatory, anti-oxidative and anti-apoptotic functions, as revealed in a human case of genetic HO-1 deficiency [25]. This enzyme participates not only in normal physiological processes, but also performs a protective role in inflammatory physiopathological conditions, such as kidney disease [26], cancer [27][28], cardiovascular disease [29], asthma [30] and inflammatory bowel diseases [4][31]. HO-1 is expressed in most cell types and tissues; however, its capacity to counteract inflammation seems to be critically dependent on its specific functions in myeloid cells and in EC [32]. In myeloid cells, HO-1 acts as a key regulator of the TLR4/TLR3/IRF3 induced production of IFN-β and primary IRF3 target genes in macrophages [33] and modulates maturation and specific functions of dendritic cells [34][35]. Moreover, HO-1 over-expression in macrophages negatively regulates the expression of diverse proinflammatory molecules and increases the expression of anti-inflammatory cytokines [36][37][38]. Among HO-1 effects on EC, it is significant to mention its ability to inhibit the expression of pro-inflammatory genes related to EC activation, such as the TNF-α-induced adhesion molecules, E-selectin and VCAM-1, via a mechanism associated with the inhibition of NF-κB activation [39]. As it was mentioned before, HO-1 cleaves the heme group, which is usually bound to a myriad of proteins and it is involved in several homeostatic functions [23]. However, elevated concentrations of heme can cause cell damage because it is a pro-oxidant molecule. It can diffuse through cell membranes and deliver a redox active iron, producing ROS [40]. Excessive amounts of these molecules are toxic and induce oxidative stress that, in turn, generates DNA and protein damage, aggregation and lipid peroxidation, triggering cells permeability and driving cell lysis and death [40].

5. HO-1 Mechanism of Action against Inflammatory Lung Diseases

There is extensive literature about the role of HO-1 in lung diseases. This protein is expressed in type II pneumocytes and in alveolar macrophages and contributes to the protection of the lung tissue. The main HO-1 inducers in the lungs are pro-inflammatory cytokines, such as TNF-α and IL-6, the heme group and nitric oxide (NO), as well as hypoxia and hyperoxia conditions [41] (Figure 1). There is sound evidence that states that HO-1 induction is a critical defense factor during acute and chronic lung processes [41][42][43].
Antioxidants 11 00276 g002 550
Figure 1. HO-1 and inflammatory lung diseases. HO-1 is expressed in pulmonary cells and confers protection against inflammatory lung diseases such as acute respiratory distress syndrome (ARDS), acute lung injury (ALI), and SARS-CoV-2 infection. Schematic representation displaying HO-1′s reaction and its products’ protective effects in the lung tissue.

6. Unveiling How HO-1 Promotes Viral Clearance

HO-1 has immunomodulatory properties on the innate immune response and there is compelling evidence suggesting that it also plays a central role in the modulation of adaptive immunity. HO-1 displays antiviral properties against a wide range of viruses [7] (Figure 2). Several reports have demonstrated that HO-1 induction is associated with the activation of the IFN pathway. However, the mechanism underlying the antiviral properties of HO-1 exerted by both its classical and non-canonical activities are yet to be fully elucidated.
Antioxidants 11 00276 g003 550
Figure 2. HO-1′s induction and its effect on different viral infections. Table containing previously reported studies about HO-1 involvement in influenza A virus (IAV), respiratory syncytial virus (RSV), human immunodeficiency virus (HIV), ebola virus (EBOV), dengue virus (DENV), zika virus (ZIKV), hepatitis C virus (HCV), hepatitis B virus (HBV), herpes simplex virus 2 (HSV-2), enterovirus 71 (EV71) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. The table includes the experimental model, HO-1 inducers, its mechanism of action, its effect and the study’s PMID. CoPP: cobalt protoporphyrin IX, DMO-CAP: 6-demethoxy-4′-O-methylcapillarisin, ROS: Reactive oxygen species, IFN: interferon, MDM: monocyte derived macrophages, BV: Biliverdin, CO: carbon monoxide, CORM-2: CO-releasing molecule-2.

7. HO-1 Induction as a Strategy against COVID-19

There are mainly two different approaches to develop antiviral therapies: (1) therapies directed against viral factors; or (2) therapies targeting the host immune system. To date, the second strategy has received increasing attention due to the fact that targeting viral factors might cause viruses to mutate, increasing the rate of resistance to antiviral drugs [44]. In contrast to the viral genome, host cells’ DNA does not have a high mutational frequency. Therefore, overpowering viral infection by targeting host factors involved in the antiviral response is conceivably an effective strategy to counteract the severe consequences, while also fighting the infection [45].
Certainly, HO-1 and its reaction products possess beneficial effects for the host during viral infections: it reduces inflammation and exerts antiviral actions. The most serious COVID-19 complications are: sepsis like inflammation, coagulopathy, and cardiovascular or respiratory complications. Furthermore, respiratory failure triggers hypoxia which, in combination with neuroinflammation, generates neurological complications [46]. When inflammation is not modulated, it turns into hyperinflammation and results in tissue damage or organ failure [47]. Enhancing HO-1 expression might help avoid the severe consequences of this disease. For example, it has been reported that HO-1 induction decreases inflammation, inhibits platelet aggregation, and increases fibrinolysis and phagocytosis, thus preventing tissue damage, thrombosis and sepsis [48]. Additionally, hemin is an activator of neuroglobin, a protein involved in oxygen transport and storage in neurons that increases oxygen’s intracellular partial pressure in neurons, and is crucial to protect neurons from hypoxic injury [49][50][51]. 

9. Conclusions

Hemin, a previously FDA and EMA approved drug for acute intermittent porphyria treatment, rises as a promising drug candidate, inducing HO-1 plasma concentration in humans, and posing a host defense advantage to fight SARS-CoV-2. Further work on optimal drug concentrations, pharmacokinetics and pharmacodynamics should be performed in order to prove hemin’s effectiveness (either alone or in combination with other drugs) to halt infection.

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