title: TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice.
abstract: The homeostasis of neutrophil granulocytes can affect the outcome of several inflammation-associated diseases including cancer. The regulation of this homeostasis is still not completely understood. We previously found that elevated systemic levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) induce an increase of neutrophils in the liver, which in turn strongly promotes liver metastasis. Here, we report that increasing systemic TIMP-1 levels were sufficient to induce neutrophilia in mice. This was not attributed to prolonged survival or direct mobilization of neutrophils. However, TIMP-1 induced enrichment of myeloid progenitors and concomitant upregulation of granulopoiesis-associated genes in the bone marrow compartment. BrdU pulse-labeling confirmed that proliferating progenitors accounted for TIMP-1-induced neutrophilia. TIMP-1 variants that dissect its protease-inhibitory from its CD63 binding function relevant for cell signaling revealed that the TIMP-1 signaling domain was necessary and sufficient to augment granulopoiesis. Consequently, ablation of the TIMP-1 receptor CD63 abolished both neutrophilia and TIMP-1-enhanced granulopoiesis in the bone marrow. Our findings reveal that elevated levels of TIMP-1 impact on neutrophil homeostasis via signaling through CD63. This may provide a link to clinical observations, where TIMP-1 correlates with high severity and bad prognosis in inflammation-associated diseases.
authors.affiliation: Institut für Molekulare Immunologie und Experimentelle Onkologie, Klinikum rechts der Isar, Technische Universität München, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Kobuch
authors.affiliation: Institut für Molekulare Immunologie und Experimentelle Onkologie, Klinikum rechts der Isar, Technische Universität München, Germany.
authors.forename: Haissi
authors.initials: H
authors.lastname: Cui
authors.affiliation: Institut für Molekulare Immunologie und Experimentelle Onkologie, Klinikum rechts der Isar, Technische Universität München, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Grünwald
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-Universität zu Kiel, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.affiliation: Institut für Molekulare Immunologie und Experimentelle Onkologie, Klinikum rechts der Isar, Technische Universität München, Germany.
authors.forename: Percy A
authors.initials: PA
authors.lastname: Knolle
authors.affiliation: Institut für Molekulare Immunologie und Experimentelle Onkologie, Klinikum rechts der Isar, Technische Universität München, Germany achim.krueger@lrz.tum.de.
authors.forename: Achim
authors.initials: A
authors.lastname: Krüger
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000235:genetics; D006098:Granulocytes; D007958:Leukocyte Count; D007964:Leukocytosis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D038042:Myelopoiesis / Q000235:genetics; D009504:Neutrophils; D015398:Signal Transduction; D060149:Tetraspanin 30 / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*
chemical_list: D060149:Tetraspanin 30; D019715:Tissue Inhibitor of Metalloproteinase-1