Chronic Iron Overload Results in Impaired Bacterial Killing of THP-1 Derived Macrophage through the Inhibition of Lysosomal Acidification.
Chronic Iron Overload Results in Impaired Bacterial Killing of THP-1 Derived Macrophage through the Inhibition of Lysosomal Acidification.
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DOI：
10.1371/journal.pone.0156713
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Shieh JJ
中科院分区：
文献类型：
--
作者：
Kao JK;Wang SC;Ho LW;Huang SW;Chang SH;Yang RC;Ke YY;Wu CY;Wang JY;Shieh JJ
铁对于生物体至关重要，铁稳态的紊乱与免疫功能的改变有关。此外，细菌感染可能会在慢性铁超负荷的情况下引起严重并发症，例如输血依赖性地中海贫血患者。单核细胞和巨噬细胞在维持全身铁稳态和防御病原体入侵方面发挥着重要作用。然而，铁过载对单核细胞和巨噬细胞功能的影响尚不清楚。我们通过持续将人类单核细胞系 (THP-1) 和 THP-1 衍生巨噬细胞 (TDM) 暴露于高水平铁 (100 μM) 中以分别产生 I-THP-1 和 I-TDM，阐明了慢性铁过载对它们的影响。我们的结果表明，铁过载不会影响 I-THP-1 的形态或粒度，但会增加 I-TDM 的粒度。对非致病性大肠杆菌 DH5α、JM109 和致病性铜绿假单胞菌的杀菌测定均表明，随着 I-TDM 中铁浓度的增加，效率降低。当细胞在含铁培养基中培养时，还发现人原代单核细胞衍生巨噬细胞（hMDM）的铜绿假单胞菌杀伤能力受损。对 I-TDM 杀菌活性的进一步研究表明，溶酶体功能障碍与溶酶体酸化抑制相关，导致溶酶体 pH 值升高、组织蛋白酶（特别是组织蛋白酶 D）翻译后加工受损以及自噬通量减少。这些发现可能解释了患有慢性铁超载的地中海贫血患者先天免疫受损的原因，表明操纵溶酶体功能作为一种新的治疗方法。
Iron is essential for living organisms and the disturbance of iron homeostasis is associated with altered immune function. Additionally, bacterial infections can cause major complications in instances of chronic iron overload, such as patients with transfusion-dependent thalassemia. Monocytes and macrophages play important roles in maintaining systemic iron homoeostasis and in defense against invading pathogens. However, the effect of iron overload on the function of monocytes and macrophages is unclear. We elucidated the effects of chronic iron overload on human monocytic cell line (THP-1) and THP-1 derived macrophages (TDM) by continuously exposing them to high levels of iron (100 μM) to create I-THP-1 and I-TDM, respectively. Our results show that iron overload did not affect morphology or granularity of I-THP-1, but increased the granularity of I-TDM. Bactericidal assays for non-pathogenic E. coli DH5α, JM109 and pathogenic P. aeruginosa all revealed decreased efficiency with increasing iron concentration in I-TDM. The impaired P. aeruginosa killing ability of human primary monocyte derived macrophages (hMDM) was also found when cells are cultured in iron contained medium. Further studies on the bactericidal activity of I-TDM revealed lysosomal dysfunction associated with the inhibition of lysosomal acidification resulting in increasing lysosomal pH, the impairment of post-translational processing of cathepsins (especially cathepsin D), and decreased autophagic flux. These findings may explain the impaired innate immunity of thalassemic patients with chronic iron overload, suggesting the manipulation of lysosomal function as a novel therapeutic approach.