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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.
AuthorsJulia Kobuch, Haissi Cui, Barbara Grünwald, Paul Saftig, Percy A Knolle, Achim Krüger
JournalHaematologica (Haematologica) Vol. 100 Issue 8 Pg. 1005-13 (Aug 2015) ISSN: 1592-8721 [Electronic] Italy
PMID26001794 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright© Ferrata Storti Foundation.
Chemical References
  • Tetraspanin 30
  • Tissue Inhibitor of Metalloproteinase-1
Topics
  • Animals
  • Cell Line, Tumor
  • Cell Survival (genetics)
  • Chemotaxis, Leukocyte (genetics)
  • Granulocytes
  • Leukocyte Count
  • Leukocytosis (genetics, metabolism)
  • Mice
  • Mice, Knockout
  • Myelopoiesis (genetics)
  • Neutrophils
  • Signal Transduction
  • Tetraspanin 30 (metabolism)
  • Tissue Inhibitor of Metalloproteinase-1 (blood, genetics, metabolism)

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