Abelson tyrosine kinase controls phagosomal acidification required for killing of Mycobacterium tuberculosis in human macrophages.
Abelson tyrosine kinase controls phagosomal acidification required for killing of Mycobacterium tuberculosis in human macrophages.
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DOI：
10.4049/jimmunol.1201538
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发表时间：
2012-10-15
期刊：
影响因子：
--
通讯作者：
Stenger S
中科院分区：
文献类型：
--
作者：
Bruns H;Stegelmann F;Fabri M;Döhner K;van Zandbergen G;Wagner M;Skinner M;Modlin RL;Stenger S
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 酪氨酸激酶是细胞生长和细胞内细胞器运输的主开关，控制人类巨噬细胞中溶酶体的酸化。伊马替尼的药理抑制和 Abelson (Abl) 酪氨酸激酶的基因沉默通过增加质子泵空泡型 H+-腺苷三磷酸酶的转录和表达来降低人巨噬细胞中的溶酶体 pH 值。由于针对细胞内细菌的抗菌活性需要溶酶体酸化，因此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。生长限制取决于分枝杆菌室的酸化。伊马替尼的作用在体内也很活跃，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酸性更强。重要的是，伊马替尼治疗患者的血清引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 酪氨酸激酶的一种新功能，并提供了该调节发生在液泡型 H+-腺苷三磷酸酶水平上的证据。鉴于伊马替尼在小鼠结核病模型中的功效，以及我们发现口服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，因此有必要对伊马替尼作为结核病（特别是多药或极度耐药疾病）的补充疗法进行临床评估。
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 imatinibtreated 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 drugresistant disease, is warranted.
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影响因子：
17.1
作者：
Fabri M;Stenger S;Shin DM;Yuk JM;Liu PT;Realegeno S;Lee HM;Krutzik SR;Schenk M;Sieling PA;Teles R;Montoya D;Iyer SS;Bruns H;Lewinsohn DM;Hollis BW;Hewison M;Adams JS;Steinmeyer A;Zügel U;Cheng G;Jo EK;Bloom BR;Modlin RL
通讯作者：
Modlin RL
影响因子：
15.9
作者：
Bruns, Heiko;Meinken, Christoph;Stenger, Steffen
通讯作者：
Stenger, Steffen
影响因子：
64.8
作者：
HEISTERKAMP, N;STAM, K;GROSVELD, G
通讯作者：
GROSVELD, G
影响因子：
24.3
作者：
Daniels, J. M. A.;Vonk-Noordegraaf, A.;van Altena, R.
通讯作者：
van Altena, R.
影响因子：
3.1
作者：
Bouley, DM;Ghori, N;Ramakrishnan, L
通讯作者：
Ramakrishnan, L