Institut für Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Ulm, D-89081 Ulm, Germany.
J Immunol. 2012 Oct 15;189(8):4069-78. doi: 10.4049/jimmunol.1201538. Epub 2012 Sep 17.
The mechanisms that regulate the acidification of intracellular compartments are key to host defense against pathogens. In this paper, we demonstrate that Abl tyrosine kinase, a master switch for cell growth and trafficking of intracellular organelles, controls the acidification of lysosomes in human macrophages. Pharmacological inhibition by imatinib and gene silencing of Abelson (Abl) tyrosine kinase reduced the lysosomal pH in human macrophages by increasing the transcription and expression of the proton pumping enzyme vacuolar-type H(+)-adenosine triphosphatase. Because lysosomal acidification is required for antimicrobial activity against intracellular bacteria, we determined the effect of imatinib on the growth of the major human pathogen Mycobacterium tuberculosis. Imatinib limited the multiplication of M. tuberculosis, and growth restriction was dependent on acidification of the mycobacterial compartment. The effects of imatinib were also active in vivo because circulating monocytes from imatinib-treated leukemia patients were more acidic than monocytes from control donors. Importantly, sera from imatinib-treated patients triggered acidification and growth restriction of M. tuberculosis in macrophages. In summary, our results identify the control of phagosomal acidification as a novel function of Abl tyrosine kinase and provide evidence that the regulation occurs on the level of the vacuolar-type H(+)-adenosine triphosphatase. Given the efficacy of imatinib in a mouse model of tuberculosis and our finding that orally administered imatinib increased the ability of human serum to trigger growth reduction of intracellular M. tuberculosis, clinical evaluation of imatinib as a complementary therapy of tuberculosis, in particular multidrug or extremely drug-resistant disease, is warranted.
调节细胞内区室酸化的机制是宿主防御病原体的关键。在本文中，我们证明 Abl 酪氨酸激酶（细胞生长和细胞内细胞器运输的主开关）控制人巨噬细胞溶酶体的酸化。通过伊马替尼的药理学抑制和 Abelson（Abl）酪氨酸激酶的基因沉默，通过增加质子泵酶液泡型 H(+)-三磷酸腺苷酶的转录和表达，降低人巨噬细胞中的溶酶体 pH 值。因为溶酶体酸化是对抗细胞内细菌的抗菌活性所必需的，所以我们确定了伊马替尼对主要人类病原体结核分枝杆菌生长的影响。伊马替尼限制了结核分枝杆菌的繁殖，并且生长限制依赖于分枝杆菌区室的酸化。伊马替尼的作用在体内也是有效的，因为来自伊马替尼治疗的白血病患者的循环单核细胞比来自对照供体的单核细胞更酸性。重要的是，来自伊马替尼治疗患者的血清触发了巨噬细胞中结核分枝杆菌的酸化和生长限制。总之，我们的结果确定了吞噬体酸化的控制是 Abl 酪氨酸激酶的一个新功能，并提供了证据表明该调节发生在液泡型 H(+)-三磷酸腺苷酶的水平上。鉴于伊马替尼在结核分枝杆菌小鼠模型中的疗效以及我们发现口服给予伊马替尼增加了人血清触发细胞内结核分枝杆菌生长减少的能力，伊马替尼作为结核病的补充治疗，特别是多药或极端耐药疾病的临床评估是合理的。
