Megakaryocytes compensate for Kit insufficiency in murine arthritis
Pierre Cunin, … , Eric Boilard, Peter A. Nigrovic
Pierre Cunin, … , Eric Boilard, Peter A. Nigrovic
Published April 4, 2017
Citation Information: J Clin Invest. 2017;127(5):1714-1724. https://doi.org/10.1172/JCI84598.
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Research Article Immunology Inflammation

Megakaryocytes compensate for Kit insufficiency in murine arthritis

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

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Figure 3

A nonneutrophil IL-1–expressing marrow lineage bypasses the requirement for MC in W/Wv mice.

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A nonneutrophil IL-1–expressing marrow lineage bypasses the requirement ...
(A) W/Wv mice were injected i.v. with purified B6 bone marrow neutrophils (2 donors/d on days 0–4) or saline control as well as 150 μl i.p. K/BxN serum on days 0 and 2 (n = 5/group; 1 of 2 similar experiments shown). (B) W/Wv mice received whole B6, Wsh, Gfi1–/–, or Il1–/– bone marrow by tail vein (1 donor per 2 recipients), and arthritis was initiated 14 days later as above. Left, clinical scoring (mock engrafted vs. B6 engrafted, P = 0.0001; mock engrafted vs. Wsh engrafted, P = 0.0117; mock engrafted vs. Gfi1–/– engrafted, P = 0.004; mock engrafted vs. Il1–/– engrafted, P = NS). Right, ankle and wrist thickness change (mock engrafted vs. B6 engrafted, P = 0.012; mock engrafted vs. Wsh engrafted, P = 0.03; mock engrafted vs. Gfi1–/– engrafted, P = 0.038; mock engrafted vs. Il1–/– engrafted, P = NS). Mock engrafted, n = 20; B6 engrafted, n = 16; Wsh engrafted, n = 15; Gfi1–/– engrafted, n = 10; Il1–/– engrafted, n = 16; pool of 2–3 experiments.