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 IFNγ production by T lymphocytes and NOS2 expression underlie this T-cell requirement and that HO-1 inhibition potentiates IFNγ-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 IFNγ/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.

结核分枝杆菌(Mtb) 感染诱导血红素降解酶血红素加氧酶-1 (HO-1) 的肺表达。我们之前已经表明，实验性结核病中 HO-1 活性的药理学抑制会导致细菌负荷减少，而且出乎意料的是，这种结果取决于 T 淋巴细胞的存在。在这里，我们通过证明 T 淋巴细胞产生的 IFNγ 和 NOS2 表达是这种 T 细胞需求的基础，并且 HO-1 抑制增强了 IFNγ 诱导的巨噬细胞对 Mtb 的 NOS2 依赖性体外控制，从而扩展了这些发现。在 HO-1 的血红素降解产物（胆绿素、一氧化碳和铁）中，只有补铁可以恢复 HO-1 抑制诱导的细菌控制增强，并且这种逆转与 NOS2 表达和 NO 产生减少有关。此外，我们发现 HO-1 抑制导致体外 Mtb 感染的巨噬细胞中不稳定铁水平降低，并减少体内 Mtb 感染肺中的铁积累。这些结果共同表明，抑制 HO-1 对 Mtb 感染的治疗结果对 T 淋巴细胞的依赖性反映了该酶在生成抑制 T 细胞介导的 IFNγ/NOS2 依赖性细菌控制的铁中的作用。从更广泛的角度来看，我们的研究结果强调了铁代谢和适应性免疫之间的串扰在决定感染结果方面的重要性。这些结果共同表明，抑制 HO-1 对 Mtb 感染的治疗结果对 T 淋巴细胞的依赖性反映了该酶在生成抑制 T 细胞介导的 IFNγ/NOS2 依赖性细菌控制的铁中的作用。从更广泛的角度来看，我们的研究结果强调了铁代谢和适应性免疫之间的串扰在决定感染结果方面的重要性。这些结果共同表明，抑制 HO-1 对 Mtb 感染的治疗结果对 T 淋巴细胞的依赖性反映了该酶在生成抑制 T 细胞介导的 IFNγ/NOS2 依赖性细菌控制的铁中的作用。从更广泛的角度来看，我们的研究结果强调了铁代谢和适应性免疫之间的串扰在决定感染结果方面的重要性。