Heme oxygenase-1 promotes granuloma development and protects against dissemination of mycobacteria

Abstract

Non-tuberculous mycobacterial (NTM) infections occur in both immunocompromised and immunocompetent hosts and are an increasingly recognized cause of morbidity and mortality. The hallmark of pulmonary mycobacterial infections is the formation of granuloma in the lung. Our study focuses on the role of heme oxygenase-1 (HO-1), a cytoprotective enzyme, in the regulation of granuloma development and maturation following infection with Mycobacterium avium. We examined the role of HO-1 in regulating monocyte chemoattractant protein-1 (MCP-1) and chemokine receptor 2 (CCR2), two molecules involved in monocyte-macrophage cell trafficking after infection. We showed that RAW 264.7 mouse monocytes exposed to M. avium expressed HO-1 and MCP-1. Inhibition of heme oxygenase by zinc protoporphyrin-IX led to inhibition of MCP-1 and increased expression of CCR2, its cognate receptor. HO-1-/- mice did not develop organized granuloma in their lungs, had higher lung colony forming unit of M. avium when infected with intratracheal M. avium, and had loose collections of inflammatory cells in the lung parenchyma. Mycobacteria were found only inside defined granulomas but not outside granuloma in the lungs of HO-1+/+ mice. In HO-1-/- mice, mycobacteria were also found in the liver and spleen and showed increased mortality. Peripheral blood monocytes isolated from GFP+ mice and given intravenously to HO-1+/+ mice localized into tight granulomas, while in HO-1-/- mice they remained diffusely scattered in areas of parenchymal inflammation. Higher MCP-1 levels were found in bronchoalveolar lavage fluid (BALF) of M. avium infected HO-1-/- mice and CCR2 expression was higher in HO-1-/- alveolar macrophages when compared to HO-1+/+ mice. CCR2 expression localized to granuloma in HO-1+/+ mice but not in the HO-1-/- mice. These findings strongly suggest that HO-1 plays a protective role in the control of M. avium infection.

Heme Oxygenase-1 and Carbon Monoxide Promote Burkholderia pseudomallei Infection

“…Additionally, we observed a significant increase in HO-1 expression in both murine macrophage RAW264.7 and hepatoma Hepa1-6 cells (unpublished data). This is consistent with previously published studies demonstrating an upregulation of HO-1 mRNA and/or protein expression in response to bacterial (29,(40)(41)(42)(43)(44)(45) or parasitic (26,27,46) infections and might be a general response of infected host cells.…”

Heme Catabolism by Heme Oxygenase-1 Confers Host Resistance to Mycobacterium Infection

“…The MCP-1/CCL2 concentration in plasma, liver, and spleen was higher in Hmox1 Ϫ/Ϫ than in Hmox1 ϩ/ϩ mice (Fig. 2), which is in keeping with a recent report suggesting that HO-1 controls MCP-1/CCL2 during Mycobacterium infection (32). This was also the case for CCL3, but only in the spleen (Fig.…”

Distal Hydrogen-bonding Interactions in Ligand Sensing and Signaling by Mycobacterium tuberculosis DosS

“…Like any infection, tuberculosis leads to a host immune response resulting in recruitment of lymphocytes and macrophages (2). This process is associated with high levels of NO and CO produced by inducible nitric-oxide synthase and heme oxygenase-1 (HO-1), respectively, as part of the defense mechanism of macrophages (3)(4)(5). The ability of M. tuberculosis to successfully survive within the host for years in a clinically undetectable dormant state known as non-replicating persistence (NRP), 3 in which it is resistant to most of the currently available treatments, makes it of paramount importance to elucidate this defense strategy (6).…”

“…The ability of M. tuberculosis to successfully survive within the host for years in a clinically undetectable dormant state known as non-replicating persistence (NRP), 3 in which it is resistant to most of the currently available treatments, makes it of paramount importance to elucidate this defense strategy (6). The mechanism of NRP is not fully understood; however, hypoxia (7,8), high CO and NO levels (5,9), nutrient deprivation (10), and the pH of the microenvironment (11) are among the factors leading to NRP. It has been shown that NRP can initiate changes in energy metabolism and cellular signaling pathways that lead to M. tuberculosis growth arrest.…”