title: Chronic Iron Overload Results in Impaired Bacterial Killing of THP-1 Derived Macrophage through the Inhibition of Lysosomal Acidification.
abstract: 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.
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.|Pediatric Department, Children's Hospital, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Jun-Kai
authors.initials: JK
authors.lastname: Kao
authors.affiliation: Pediatric Department, Children's Hospital, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Shih-Chung
authors.initials: SC
authors.lastname: Wang
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.|Pediatric Department, Children's Hospital, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Ho
authors.affiliation: Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Shi-Wei
authors.initials: SW
authors.lastname: Huang
authors.affiliation: Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan.
authors.forename: Shu-Hao
authors.initials: SH
authors.lastname: Chang
authors.affiliation: Pediatric Department, Children's Hospital, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Rei-Cheng
authors.initials: RC
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Yu-Yuan
authors.initials: YY
authors.lastname: Ke
authors.affiliation: Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Chun-Ying
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Allergy and Clinical Immunology Research (ACIR) Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|China Medical University Children's Hospital, Taichung, Taiwan.
authors.forename: Jiu-Yao
authors.initials: JY
authors.lastname: Wang
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.|Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan.|Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Jeng-Jer
authors.initials: JJ
authors.lastname: Shieh
mesh_terms: D002402:Cathepsin D / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004926:Escherichia coli / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007501:Iron / Q000378:metabolism / Q000494:pharmacology*; D019190:Iron Overload / Q000276:immunology*; D008247:Lysosomes / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D007501:Iron; C533922:CTSD protein, human; D002402:Cathepsin D