Heme oxygenase-1 inhibition promotes IFN$γ$- and NOS2-mediated control of Mycobacterium tuberculosis infection. Costa, D. L., Amaral, E. P., Namasivayam, S., Mittereder, L. R., Fisher, L., Bonfim, C. C., Sardinha-Silva, A., Thompson, R. W., Hieny, S. E., Andrade, B. B., & Sher, A. Mucosal Immunology, 14:253–266, Springer Nature, aug, 2021. ![Heme oxygenase-1 inhibition promotes IFN$γ$- and NOS2-mediated control of Mycobacterium tuberculosis infection [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex Mycobacterium tuberculosis (Mtb) infection induces pulmonary expression of the heme-degrading enzyme heme oxygenase-1 (HO-1). We have previously shown that pharmacological inhibition of HO-1 activity in experimental tuberculosis results in decreased bacterial loads and unexpectedly that this outcome depends on the presence of T lymphocytes. Here, we extend these findings by demonstrating that IFN$γ$ production by T lymphocytes and NOS2 expression underlie this T-cell requirement and that HO-1 inhibition potentiates IFN$γ$-induced NOS2-dependent control of Mtb by macrophages in vitro. Among the products of heme degradation by HO-1 (biliverdin, carbon monoxide, and iron), only iron supplementation reverted the HO-1 inhibition-induced enhancement of bacterial control and this reversal was associated with decreased NOS2 expression and NO production. In addition, we found that HO-1 inhibition results in decreased labile iron levels in Mtb-infected macrophages in vitro and diminished iron accumulation in Mtb-infected lungs in vivo. Together these results suggest that the T-lymphocyte dependence of the therapeutic outcome of HO-1 inhibition on Mtb infection reflects the role of the enzyme in generating iron that suppresses T-cell-mediated IFN$γ$/NOS2-dependent bacterial control. In broader terms, our findings highlight the importance of the crosstalk between iron metabolism and adaptive immunity in determining the outcome of infection.
@article{Costa2020,
abstract = {Mycobacterium tuberculosis (Mtb) infection induces pulmonary expression of the heme-degrading enzyme heme oxygenase-1 (HO-1). We have previously shown that pharmacological inhibition of HO-1 activity in experimental tuberculosis results in decreased bacterial loads and unexpectedly that this outcome depends on the presence of T lymphocytes. Here, we extend these findings by demonstrating that IFN$\gamma$ production by T lymphocytes and NOS2 expression underlie this T-cell requirement and that HO-1 inhibition potentiates IFN$\gamma$-induced NOS2-dependent control of Mtb by macrophages in vitro. Among the products of heme degradation by HO-1 (biliverdin, carbon monoxide, and iron), only iron supplementation reverted the HO-1 inhibition-induced enhancement of bacterial control and this reversal was associated with decreased NOS2 expression and NO production. In addition, we found that HO-1 inhibition results in decreased labile iron levels in Mtb-infected macrophages in vitro and diminished iron accumulation in Mtb-infected lungs in vivo. Together these results suggest that the T-lymphocyte dependence of the therapeutic outcome of HO-1 inhibition on Mtb infection reflects the role of the enzyme in generating iron that suppresses T-cell-mediated IFN$\gamma$/NOS2-dependent bacterial control. In broader terms, our findings highlight the importance of the crosstalk between iron metabolism and adaptive immunity in determining the outcome of infection.},
author = {Costa, Diego L. and Amaral, Eduardo P. and Namasivayam, Sivaranjani and Mittereder, Lara R. and Fisher, Logan and Bonfim, Caio C. and Sardinha-Silva, Aline and Thompson, Robert W. and Hieny, Sara E. and Andrade, Bruno B. and Sher, Alan},
doi = {10.1038/s41385-020-00342-x},
issn = {19353456},
journal = {Mucosal Immunology},
keywords = {Allergology,Antibodies,Biomedicine,Gastroenterology,Immunology,fund{\_}not{\_}ack,general,original},
mendeley-tags = {fund{\_}not{\_}ack,original},
month = {aug},
pages = {253--266},
pmid = {32862202},
publisher = {Springer Nature},
title = {{Heme oxygenase-1 inhibition promotes IFN$\gamma$- and NOS2-mediated control of Mycobacterium tuberculosis infection}},
url = {https://www.nature.com/articles/s41385-020-00342-x},
volume = {14},
year = {2021}
}
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Here, we extend these findings by demonstrating that IFN$γ$ production by T lymphocytes and NOS2 expression underlie this T-cell requirement and that HO-1 inhibition potentiates IFN$γ$-induced NOS2-dependent control of Mtb by macrophages in vitro. Among the products of heme degradation by HO-1 (biliverdin, carbon monoxide, and iron), only iron supplementation reverted the HO-1 inhibition-induced enhancement of bacterial control and this reversal was associated with decreased NOS2 expression and NO production. In addition, we found that HO-1 inhibition results in decreased labile iron levels in Mtb-infected macrophages in vitro and diminished iron accumulation in Mtb-infected lungs in vivo. Together these results suggest that the T-lymphocyte dependence of the therapeutic outcome of HO-1 inhibition on Mtb infection reflects the role of the enzyme in generating iron that suppresses T-cell-mediated IFN$γ$/NOS2-dependent bacterial control. 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