Heme Oxygenase-1 as a Pharmacological Target for Host-Directed Therapy to Limit Tuberculosis Associated Immunopathology

Abstract

Excessive inflammation and tissue damage are pathological hallmarks of chronic pulmonary tuberculosis (TB). Despite decades of research, host regulation of these clinical consequences is poorly understood. A sustained effort has been made to understand the contribution of heme oxygenase-1 (HO-1) to this process. HO-1 is an essential cytoprotective enzyme in the host that controls inflammation and oxidative stress in many pathological conditions. While HO-1 levels are upregulated in animals and patients infected with Mycobacterium tuberculosis (Mtb), how it regulates host responses and disease pathology during TB remains unclear. This lack of clarity is due in part to contradictory studies arguing that HO-1 induction contributes to both host resistance as well as disease progression. In this review, we discuss these conflicting studies and the role of HO-1 in modulating myeloid cell functions during Mtb disease progression. We argue that HO-1 is a promising target for host-directed therapy to improve TB immunopathology.

Keywords: Mycobacterium tuberculosis; TB; glycolysis; heme oxygenase-1; immunometabolism; immunopathology; macrophages; neutrophils; pentose phosphate pathway; reactive nitrogen species; reactive oxygen species.

Figure 1

Overview of Heme oxygenase-1 (HO-1) enzymatic reaction and physiological roles of its enzymatic by-products: HO-1 is induced under various physiological challenges including stress, hypoxia, ROS, heat shock and microbial infections. The HO-1 catabolizes heme into equimolar ratios of CO, iron and biliverdin, using NADPH and cytochrome p450 reductase. Biliverdin is further converted into bilirubin by biliverdin reductase. The free iron is stored by the iron storage enzyme ferritin. CO, bilirubin and ferritin drives several host protective physiological roles including anti-inflammation, cryoprotection and anti-oxidation. Physiological roles of each by-product are in red font.

Figure 2

Overview of HO-1 mediated regulation of (A) macrophages, (B) neutrophils. (A) HO-1 improves mitochondrial respiration which in turn can modulate macrophage phenotype towards M2 phenotype. In addition, increase in HO-1 levels correlates with decreased MMP and RNI levels. (B) In neutrophils, HO-1 controls oxidative burst, decreases NADPH activation and shifts the neutrophil metabolism towards PPP. In addition, HO-1 also reduced the formation of NETosis and regulates neutrophil trafficking and recruitment. Together, these responses result in decreased inflammation and tissue pathology.

Figure 3

Model for the impact of HO-1 levels in the outcome of TB immunopathology. During late stages of TB disease, there is a significant hemorrhage and heme release in the surroundings of disease which causes reduction in HO-1 levels and its enzymatic activity. Heme, a very potent oxidant molecule, causes significant tissue damage. This is accompanied by uncontrolled infiltration of myeloid cells and their pro-inflammatory functions, causing significantly elevated levels of ROI, RNI and ONOO⁻ and exaggerate the TB immunopathology. Conversely, using HO-1 as HDT target and inducing its levels, especially during late stages of TB could provide host cytoprotection by improving heme catalysis, decreasing immune cell infiltration and supporting anti-inflammation and tissue repair.