title: The Thyroid Hormone Inactivating Enzyme Type 3 Deiodinase is Present in Bactericidal Granules and the Cytoplasm of Human Neutrophils.
abstract: Neutrophils are important effector cells of the innate immune system. Thyroid hormone (TH) is thought to play an important role in their function. Intracellular TH levels are regulated by the deiodinating enzymes. The TH-inactivating type 3 deiodinase (D3) is expressed in infiltrating murine neutrophils, and D3 knockout mice show impaired bacterial killing upon infection. This suggests that D3 plays an important role in the bacterial killing capacity of neutrophils. The mechanism behind this effect is unknown. We aimed to assess the presence of D3 in human neutrophils, and determine its subcellular localization using confocal and electron microscopy, because this could give important clues about its function in these cells. D3 appeared to be present in the cytoplasm and in myeloperoxidase containing azurophilic granules and as well as lactoferrin containing specific granules within human neutrophils. This subcellular localization did not change upon activation of the cells. D3 is observed intracellularly during neutrophil extracellular trap formation, followed by a reduction of D3 staining after release of the neutrophil extracellular traps into the extracellular space. At the transcriptional level, human neutrophils expressed additional essential elements of TH metabolism, including TH transporters and TH receptors. Here, we demonstrate the presence and subcellular location of D3 in human neutrophils for the first time and propose a model, in which D3 plays a role in the bacterial killing capacity of neutrophils either through generation of iodide for the myeloperoxidase system or through modulation of intracellular TH bioavailability.
authors.affiliation: Department of Endocrinology and Metabolism (A.H.v.d.S., F.F.B., E.F., A.B.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Cell Biology and Histology (W.T., N.N.v.d.W.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Department of Clinical Medicine and Surgery (M.D., D.S.), University of Naples Federico II, Naples, Italy.
authors.forename: Anne H
authors.initials: AH
authors.lastname: van der Spek
authors.affiliation: Department of Endocrinology and Metabolism (A.H.v.d.S., F.F.B., E.F., A.B.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Cell Biology and Histology (W.T., N.N.v.d.W.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Department of Clinical Medicine and Surgery (M.D., D.S.), University of Naples Federico II, Naples, Italy.
authors.forename: Flavia F
authors.initials: FF
authors.lastname: Bloise
authors.affiliation: Department of Endocrinology and Metabolism (A.H.v.d.S., F.F.B., E.F., A.B.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Cell Biology and Histology (W.T., N.N.v.d.W.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Department of Clinical Medicine and Surgery (M.D., D.S.), University of Naples Federico II, Naples, Italy.
authors.forename: Wikky
authors.initials: W
authors.lastname: Tigchelaar
authors.affiliation: Department of Endocrinology and Metabolism (A.H.v.d.S., F.F.B., E.F., A.B.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Cell Biology and Histology (W.T., N.N.v.d.W.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Department of Clinical Medicine and Surgery (M.D., D.S.), University of Naples Federico II, Naples, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Dentice
authors.affiliation: Department of Endocrinology and Metabolism (A.H.v.d.S., F.F.B., E.F., A.B.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Cell Biology and Histology (W.T., N.N.v.d.W.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Department of Clinical Medicine and Surgery (M.D., D.S.), University of Naples Federico II, Naples, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Salvatore
authors.affiliation: Department of Endocrinology and Metabolism (A.H.v.d.S., F.F.B., E.F., A.B.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Cell Biology and Histology (W.T., N.N.v.d.W.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Department of Clinical Medicine and Surgery (M.D., D.S.), University of Naples Federico II, Naples, Italy.
authors.forename: Nicole N
authors.initials: NN
authors.lastname: van der Wel
authors.affiliation: Department of Endocrinology and Metabolism (A.H.v.d.S., F.F.B., E.F., A.B.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Cell Biology and Histology (W.T., N.N.v.d.W.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Department of Clinical Medicine and Surgery (M.D., D.S.), University of Naples Federico II, Naples, Italy.
authors.forename: Eric
authors.initials: E
authors.lastname: Fliers
authors.affiliation: Department of Endocrinology and Metabolism (A.H.v.d.S., F.F.B., E.F., A.B.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Cell Biology and Histology (W.T., N.N.v.d.W.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Department of Clinical Medicine and Surgery (M.D., D.S.), University of Naples Federico II, Naples, Italy.
authors.forename: Anita
authors.initials: A
authors.lastname: Boelen
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism; D065206:Extracellular Traps / Q000378:metabolism; D005260:Female; D006801:Humans; D007453:Iodide Peroxidase / Q000378:metabolism*; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000900:Anti-Bacterial Agents; D013963:Thyroid Hormones; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase