Details

Autor(en) / Beteiligte

• Cunin, Pierre
• Penke, Loka R
• Thon, Jonathan N
• Monach, Paul A
• Jones, Tatiana
• Chang, Margaret H
• Chen, Mary M
• Melki, Imene
• Lacroix, Steve
• Iwakura, Yoichiro
• Ware, Jerry
• Gurish, Michael F
• Italiano, Joseph E
• Boilard, Eric
• Nigrovic, Peter A

Titel

Megakaryocytes compensate for Kit insufficiency in murine arthritis

Ist Teil von

• The Journal of clinical investigation, 2017-05, Vol.127 (5), p.1714

Ort / Verlag

American Society for Clinical Investigation

Erscheinungsjahr

2017

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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: [Kit.sup.Wsh/Wsh], which develops robust arthritis, and [Kit.sup.W/Wv], which does not. Reciprocal bone marrow transplantation between [Kit.sup.W/Wv] and [Kit.sup.Wsh/Wsh] mice revealed that arthritis resistance reflects a hematopoietic defect in addition to mast cell deficiency. In [Kit.sup.W/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 [Kit.sup.W/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 [Kit.sup.W/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 [Kit.sup.W/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.