Heme oxygenase-1 inhibition promotes IFN$\gamma$- and NOS2-mediated control of Mycobacterium tuberculosis infection

Heme oxygenase-1 inhibition promotes IFN$\gamma$- and NOS2-mediated control of Mycobacterium tuberculosis infection. Costa, D., Amaral, E., Namasivayam, S., Mittereder, L., Fisher, L., Bonfim, C., Sardinha-Silva, A., Thompson, R., Hieny, S., Andrade, B., Andrade, B., & Sher, A. Mucosal Immunology, 14(1):253–266, 2021.
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$\gamma$ 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.

@article{Costa2021b,
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, D.L. and Amaral, E.P. and Namasivayam, S. and Mittereder, L.R. and Fisher, L. and Bonfim, C.C. and Sardinha-Silva, A. and Thompson, R.W. and Hieny, S.E. and Andrade, B.B. and Andrade, B.B. and Sher, A.},
doi = {10.1038/s41385-020-00342-x},
journal = {Mucosal Immunology},
number = {1},
pages = {253--266},
title = {{Heme oxygenase-1 inhibition promotes IFN$\gamma$- and NOS2-mediated control of Mycobacterium tuberculosis infection}},
volume = {14},
year = {2021}
}

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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. 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