title: The role of autophagy in asparaginase-induced immune suppression of macrophages.
abstract: Erwinia asparaginase, a bacteria-derived enzyme drug, has been used in the treatment of various cancers, especially acute lymphoblastic leukemia (ALL). One of the most significant side effects associated with asparaginase administration is immune suppression, which limits its application in clinic. Macrophages are phagocytic immune cells and have a central role in inflammation and host defense. We reported here that asparaginase disturbed the function of macrophages including phagocytosis, proliferation, ROS and nitric oxide secretion, interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) secretion, and major histocompatibility complex II (MHC-II) molecule expression, thus induced immune suppression in interferon-γ and lipopolysaccharide-stimulated macrophages. We also observed that asparaginase inhibited autophagy in macrophages via activating Akt/mTOR and suppressing Erk1/2 signaling pathway as evidenced by less formation of autophagosomes, downregulation of autophagy-related protein LC3-II, and decreased number of autophagy-like vacuoles. Further study discovered that treatment with autophagy inhibitor 3-MA in place of asparaginase on activated macrophages could also downregulate phagocytosis, cytokine secretion, and MHC-II expression. Moreover, incubation with autophagy inducer trehalose restored the capacity of phagocytosis, IL-6 and TNF-α secretion, and MHC-II expression in macrophages. These results prove the important role of autophagy in the function of macrophages, and activation of autophagy can overcome asparaginase-induced immune suppression in macrophages.
authors.affiliation: Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P. R. China.|Department of Pharmacy, Ruijin Hospital Luwan Branch, Shanghai, 200020, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Song
authors.affiliation: Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P. R. China.|Department of Pharmacy, Huadong Hospital, Fudan University, Shanghai, 200040, P.R. China.
authors.forename: Ziyu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P. R. China.
authors.forename: Xuyao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P. R. China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P. R. China.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P. R. China.
authors.forename: Qicheng
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P. R. China.
authors.forename: Shaofei
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P. R. China.|Department of Analytical Science, Sunshine Guojian Pharmaceutical (Shanghai) Co. Ltd, Shanghai, 201203, P.R. China.
authors.forename: Peipei
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P. R. China.
authors.forename: Jingyun
authors.initials: J
authors.lastname: Luan
authors.affiliation: Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P. R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Ye
authors.affiliation: Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P. R. China.
authors.forename: Dianwen
authors.initials: D
authors.lastname: Ju
mesh_terms: D000818:Animals; D001215:Asparaginase / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D001426:Bacterial Proteins / Q000494:pharmacology*; D002478:Cells, Cultured; D004885:Erwinia / Q000201:enzymology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; C508600:IL6 protein, human; D007166:Immunosuppressive Agents; D015850:Interleukin-6; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D001215:Asparaginase