title: Granulocyte functions are independent of arginine availability.
abstract: Arginine depletion via myeloid cell arginase is critically involved in suppression of the adaptive immune system during cancer or chronic inflammation. On the other hand, arginine depletion is being developed as a novel anti-tumor metabolic strategy to deprive arginine-auxotrophic cancer cells of this amino acid. In human immune cells, arginase is mainly expressed constitutively in PMNs. We therefore purified human primary PMNs from healthy donors and analyzed PMN function as the main innate effector cell and arginase producer in the context of arginine deficiency. We demonstrate that human PMN viability, activation-induced IL-8 synthesis, chemotaxis, phagocytosis, generation of ROS, and fungicidal activity are not impaired by the absence of arginine in vitro. Also, profound pharmacological arginine depletion in vivo via ADI-PEG20 did not inhibit PMN functions in a mouse model of pulmonary invasive aspergillosis; PMN invasion into the lung, activation, and successful PMN-dependent clearance of Aspergillus fumigatus and survival of mice were not impaired. These novel findings add to a better understanding of immunity during inflammation-associated arginine depletion and are also important for the development of therapeutic arginine depletion as anti-metabolic tumor therapy.
authors.affiliation: Institute of Immunology, University of Heidelberg, Germany; Department of Neonatology and.
authors.forename: Katharina
authors.initials: K
authors.lastname: Kapp
authors.affiliation: Institute of Immunology.
authors.forename: Steve
authors.initials: S
authors.lastname: Prüfer
authors.affiliation: Third Department of Medicine (Hematology, Oncology, and Pneumology).
authors.forename: Christian S
authors.initials: CS
authors.lastname: Michel
authors.affiliation: Department of Pharmacology, and.
authors.forename: Alice
authors.initials: A
authors.lastname: Habermeier
authors.affiliation: Third Department of Medicine (Hematology, Oncology, and Pneumology).
authors.forename: Claudia
authors.initials: C
authors.lastname: Luckner-Minden
authors.affiliation: Institute of Immunology, University of Heidelberg, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.affiliation: Polaris Pharmaceuticals, San Diego, California, USA; and.
authors.forename: John
authors.initials: J
authors.lastname: Bomalaski
authors.affiliation: Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany;
authors.forename: Claus-Dieter
authors.initials: CD
authors.lastname: Langhans
authors.affiliation: Section of Immunology, Department of Medicine, Imperial College, London, United Kingdom.
authors.forename: Pascale
authors.initials: P
authors.lastname: Kropf
authors.affiliation: Section of Immunology, Department of Medicine, Imperial College, London, United Kingdom.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Müller
authors.affiliation: Department of Pharmacology, and.
authors.forename: Ellen I
authors.initials: EI
authors.lastname: Closs
authors.affiliation: Third Department of Medicine (Hematology, Oncology, and Pneumology), Research Center for Immunology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany;
authors.forename: Markus P
authors.initials: MP
authors.lastname: Radsak
authors.affiliation: Third Department of Medicine (Hematology, Oncology, and Pneumology), Department of Neonatology and munder@uni-mainz.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Munder
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001119:Arginase / Q000097:blood / Q000502:physiology; D001120:Arginine / Q000032:analysis / Q000494:pharmacology / Q000502:physiology*; D001232:Aspergillus fumigatus / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D002956:Citrulline / Q000032:analysis; D006801:Humans; D006867:Hydrolases / Q000494:pharmacology; D007113:Immunity, Innate; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D010587:Phagocytosis; D011092:Polyethylene Glycols / Q000494:pharmacology; D061251:Primary Cell Culture; D055732:Pulmonary Aspergillosis / Q000276:immunology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst
chemical_list: D000970:Antineoplastic Agents; D016209:Interleukin-8; D017382:Reactive Oxygen Species; D002956:Citrulline; D011092:Polyethylene Glycols; D001120:Arginine; D006867:Hydrolases; D001119:Arginase; C512527:ADI PEG20
keywords: arginase; immunosuppression; innate immunity; neutrophil