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
J Clin Invest. 2017 May 1;127(5):1714-1724. doi: 10.1172/JCI84598. Epub 2017 Apr 4.
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.
生长因子受体Kit参与造血和非造血发育。携带Kit缺陷的小鼠缺乏肥大细胞；然而，携带不同Kit等位基因的品系表现出不同的表型。在此，我们研究了两种肥大细胞缺陷小鼠品系对IgG介导的关节炎敏感性差异的潜在因素：KitWsh/Wsh小鼠会发生严重关节炎，而KitW/Wv小鼠则不会。KitW/Wv和KitWsh/Wsh小鼠之间的相互骨髓移植表明，除了肥大细胞缺陷外，关节炎抗性还反映了造血缺陷。在KitW/Wv小鼠中，对IgG介导的关节炎易感性的恢复不依赖于中性粒细胞，但需要IL-1以及血小板/巨核细胞标志物NF-E2和糖蛋白VI。在KitW/Wv小鼠中，血小板数量与野生型动物相似且功能完整，野生型血小板的转移并未恢复关节炎易感性。这些数据表明巨核细胞具有不依赖血小板的作用，巨核细胞是一种依赖Kit的谱系，在KitW/Wv小鼠中选择性缺陷。巨核细胞直接分泌IL-1，并作为循环微粒的组成部分，以IL-1依赖的方式激活滑膜成纤维细胞。野生型而非IL-1缺陷型巨核细胞的转移恢复了KitW/Wv小鼠对关节炎的易感性。这些发现确定了依赖Kit的造血谱系之间的功能冗余，并确立了巨核细胞介导IL-1驱动的全身性炎症性疾病的意外能力。
