Megakaryocytes compensate for Kit insufficiency in murine arthritis
| Autor: | Steve Lacroix, Paul A. Monach, Jerry Ware, Pierre Cunin, Yoichiro Iwakura, Tatiana G. Jones, Peter A. Nigrovic, Joseph E. Italiano, Mary M. Chen, Loka R. Penke, Eric Boilard, Jonathan N. Thon, Michael F. Gurish, Imene Melki, Margaret H. Chang |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Arthritis Platelet Membrane Glycoproteins Biology Mice 03 medical and health sciences 0302 clinical medicine Megakaryocyte Growth factor receptor medicine Animals Platelet Mast Cells Mice Knockout chemistry.chemical_classification Synovial Membrane General Medicine Fibroblasts Mast cell medicine.disease Arthritis Experimental Phenotype 3. Good health Proto-Oncogene Proteins c-kit Haematopoiesis 030104 developmental biology medicine.anatomical_structure chemistry Immunoglobulin G NF-E2 Transcription Factor p45 Subunit Immunology Glycoprotein Megakaryocytes Interleukin-1 Research Article 030215 immunology |
| Zdroj: | Journal of Clinical Investigation. 127:1714-1724 |
| ISSN: | 1558-8238 0021-9738 |
| Popis: | The growth factor receptor Kit is involved in hematopoietic and nonhematopoietic development. Mice bearing Kit defects lack mast cells; however, strains bearing different Kit alleles exhibit diverse phenotypes. Herein, we investigated factors underlying differential sensitivity to IgG-mediated arthritis in 2 mast cell–deficient murine lines: KitWsh/Wsh, which develops robust arthritis, and KitW/Wv, which does not. Reciprocal bone marrow transplantation between KitW/Wv and KitWsh/Wsh mice revealed that arthritis resistance reflects a hematopoietic defect in addition to mast cell deficiency. In KitW/Wv mice, restoration of susceptibility to IgG-mediated arthritis was neutrophil independent but required IL-1 and the platelet/megakaryocyte markers NF-E2 and glycoprotein VI. In KitW/Wv mice, platelets were present in numbers similar to those in WT animals and functionally intact, and transfer of WT platelets did not restore arthritis susceptibility. These data implicated a platelet-independent role for the megakaryocyte, a Kit-dependent lineage that is selectively deficient in KitW/Wv mice. Megakaryocytes secreted IL-1 directly and as a component of circulating microparticles, which activated synovial fibroblasts in an IL-1–dependent manner. Transfer of WT but not IL-1–deficient megakaryocytes restored arthritis susceptibility to KitW/Wv mice. These findings identify functional redundancy among Kit-dependent hematopoietic lineages and establish an unanticipated capacity of megakaryocytes to mediate IL-1–driven systemic inflammatory disease. |
| Databáze: | OpenAIRE |
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