Go to JCI Insight
Jci spelled out white on transparent.20160208
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews...
    • Cellular senescence in human disease (Apr 2018)
    • Fibrosis (Jan 2018)
    • Glia and Neurodegeneration (Sep 2017)
    • Transplantation (Jun 2017)
    • Nuclear Receptors (Apr 2017)
    • Metabolism and Inflammation (Jan 2017)
    • Hypoxia and Inflammation (Oct 2016)
    • View all review series...
  • Collections
    • Recently published
    • Commentaries
    • Concise Communication
    • Editorials
    • Opinion
    • Scientific Show Stoppers
    • Top read articles
    • In-Press Preview
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

Jci only white

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Current issue
  • Past issues
  • By specialty
  • Subscribe
  • Alerts
  • Advertise
  • Contact
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • Brief Reports
  • Technical Advances
  • Commentaries
  • Editorials
  • Hindsight
  • Review series
  • Reviews
  • The Attending Physician
  • First Author Perspectives
  • Scientific Show Stoppers
  • Top read articles
  • Concise Communication
Megakaryocytes compensate for Kit insufficiency in murine arthritis
Pierre Cunin, … , Eric Boilard, Peter A. Nigrovic
Pierre Cunin, … , Eric Boilard, Peter A. Nigrovic
Published May 1, 2017
Citation Information: J Clin Invest. 2017;127(5):1714-1724. https://doi.org/10.1172/JCI84598.
View: Text | PDF
Categories: Research Article Immunology Inflammation

Megakaryocytes compensate for Kit insufficiency in murine arthritis

  • Text
  • PDF
Abstract

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.

Authors

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

×

Figure 1

Dose-dependent susceptibility of Wsh mice to K/BxN serum transfer arthritis.

Options: View larger image (or click on image) Download as PowerPoint
Dose-dependent susceptibility of Wsh mice to K/BxN serum transfer arthri...
(A–D) Male B6 (n = 19) and Wsh (n = 18) mice were treated with 150 μl i.p. K/BxN serum on days 0 and 2 and assessed for arthritis over 2 weeks. Results were pooled from 4 identical experiments using a single pooled batch of K/BxN serum. (A) Clinical scoring on a 0 to 12 scale (P = NS). (B) Ankle thickness change (P = NS). (C) Histological scoring on ankle sections (19 to 22 ankles/group, all comparisons P = NS). (D) Acute increase in ankle and wrist thickness (flare) assessed 30 minutes after injection of K/BxN serum (assessed in n = 10/group, P < 0.0001). (E) 50 μl i.p. K/BxN serum on days 0 and 2 (B6, n = 24; Wsh, n = 14 pooled from 4 experiments; P = 0.0088). **P < 0.01, ***P < 0.001.
Follow JCI: Facebook logo white Twitter logo v2 Rss icon
Copyright © 2018 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts