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.

Heme oxygenase-1 modulates ferroptosis by fine-tuning levels of intracellular iron and reactive oxygen species of macrophages in response to Bacillus Calmette-Guerin infection

“…Functionally, HO-1 catalyzes the degradation of oxidant heme into biliverdin, iron, and carbon monoxide (CO) (Szade et al, 2021). HO-1 was significantly upregulated in TB patients and in experimental animals infected with Mtb, and was a potential target for HDT for TB (Chinta et al, 2021;Uwimaana et al, 2021). In the present report, the increase of both HO-1 protein and Hemin content, a main source of iron for Mtb and host cells, was also observed in peripheral blood of TB patients, at both transcriptional and/or translational levels, which was strongly correlated with several cytokines.…”

“…However, whether the increase of apoptosis is correlated with a reduced ferroptosis needs further study. ROS generated from lipid peroxidation is crucial in cell ferroptosis (Conrad et al, 2018), and HO-1 is an essential cytoprotective enzyme that inhibits inflammation and oxidative stress (Araujo et al, 2012;Rockwood et al, 2017;Seiwert et al, 2020;Chinta et al, 2021;de Oliveira et al, 2022), and a target for HDT of TB (McLean and Munro, 2017;Chinta et al, 2021). The expression of HO-1 is largely dependent on oxidative stress in Mtb-infected cells, where an elevated expression of HO-1 is a strategy of host cells in response to oxidative stress triggered by intracellular bacteria (Rockwood et al, 2017).…”

Understanding the Reciprocal Interplay Between Antibiotics and Host Immune System: How Can We Improve the Anti-Mycobacterial Activity of Current Drugs to Better Control Tuberculosis?

“…HO-1 exerts anti-inflammatory and cytoprotective effects, although the underlying mechanisms are not fully understood (196). Several studies have investigated the host beneficial or detrimental roles of HO-1 during TB infection (95,99,(192)(193)(194)(195). Andrade et al showed that active TB patients show a negative correlation between plasma levels of HO-1 and MMP-1 (95).…”

“…In section 3, we discussed that Mtb and bactericidal anti-TB drugs cause mitochondrial dysfunction and oxidative damage in host cells, consequently ROS-mediated apoptosis as well as simultaneous activation of antioxidant mechanisms, such as the Keap1-Nrf2 signaling pathway, that may interfere with the removal of Mtb ( 88 , 89 ) A major factor involved in this mechanism is HO-1 ( 95 , 192 ). However, the detailed role of host HO-1 during the onset and pathogenesis of TB remains controversial and has not been fully elucidated ( 95 , 99 , 192 – 195 ). HO-1 exerts anti-inflammatory and cytoprotective effects, although the underlying mechanisms are not fully understood ( 196 ).…”

“…HO-1 exerts anti-inflammatory and cytoprotective effects, although the underlying mechanisms are not fully understood ( 196 ). Several studies have investigated the host beneficial or detrimental roles of HO-1 during TB infection ( 95 , 99 , 192 – 195 ). Andrade et al.…”