title: 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.forename: Pierre
authors.initials: P
authors.lastname: Cunin
authors.forename: Loka R
authors.initials: LR
authors.lastname: Penke
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Thon
authors.forename: Paul A
authors.initials: PA
authors.lastname: Monach
authors.forename: Tatiana
authors.initials: T
authors.lastname: Jones
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Chang
authors.forename: Mary M
authors.initials: MM
authors.lastname: Chen
authors.forename: Imene
authors.initials: I
authors.lastname: Melki
authors.forename: Steve
authors.initials: S
authors.lastname: Lacroix
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Jerry
authors.initials: J
authors.lastname: Ware
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gurish
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Italiano
authors.forename: Eric
authors.initials: E
authors.lastname: Boilard
authors.forename: Peter A
authors.initials: PA
authors.lastname: Nigrovic
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology; D007074:Immunoglobulin G / Q000276:immunology; D007375:Interleukin-1 / Q000235:genetics / Q000276:immunology; D008407:Mast Cells / Q000276:immunology / Q000473:pathology; D008533:Megakaryocytes / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D050984:NF-E2 Transcription Factor, p45 Subunit / Q000235:genetics / Q000276:immunology; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology
chemical_list: D007074:Immunoglobulin G; D007375:Interleukin-1; D050984:NF-E2 Transcription Factor, p45 Subunit; C494693:Nfe2 protein, mouse; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D019009:Proto-Oncogene Proteins c-kit