Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 127, Issue 5, Pages 1714-1724Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI84598
Keywords
-
Categories
Funding
- NIH [R01H168130, R21AR062328, R01AR065538, P30AR070253]
- Cogan Family Foundation
- Fundacion Bechara
- Grants-in-Aid for Scientific Research [15H05787] Funding Source: KAKEN
Ask authors/readers for more resources
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(Wsh/Wsh), which develops robust arthritis, and Kit(W/Wv), which does not. Reciprocal bone marrow transplantation between Kit(W/Wv) and Kit(Wsh/Wsh) mice revealed that arthritis resistance reflects a hematopoietic defect in addition to mast cell deficiency. In Kit(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(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(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(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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available