title: A critical role for type I IFN in arthritis development following Borrelia burgdorferi infection of mice.
abstract: Gene expression analysis previously revealed a robust IFN-responsive gene induction profile that was selectively up-regulated in Borrelia burgdorferi-infected C3H mice at 1 wk postinfection. This profile was correlated with arthritis development, as it was absent from infected, mildly arthritic C57BL/6 mice. In this report we now demonstrate that profile induction in infected C3H scid mice occurs independently of B or T lymphocyte infiltration in the joint tissue. Additionally, type I IFN receptor-blocking Abs, but not anti-IFN-gamma Abs, dramatically reduced arthritis, revealing a critical but previously unappreciated role for type I IFN in Lyme arthritis development. Certain examined IFN-inducible transcripts were also significantly diminished within joint tissue of mice treated with anti-IFNAR1, whereas expression of other IFN-responsive genes was more markedly altered by anti-IFN-gamma treatment. These data indicate that induction of the entire IFN profile is not necessary for arthritis development. These findings further tie early type I IFN induction to Lyme arthritis development, a connection not previously made. Bone marrow-derived macrophages readily induced IFN-responsive genes following B. burgdorferi stimulation, and this expression required a functional type I IFN receptor. Strikingly, induction of these genes was independent of TLRs 2,4, and 9 and of the adapter molecule MyD88. These data demonstrate that the extracellular pathogen B. burgdorferi uses a previously unidentified receptor and a pathway traditionally associated with viruses and intracellular bacteria to initiate transcription of type I IFN and IFN-responsive genes and to initiate arthritis development.
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Miller
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.forename: Jiantao
authors.initials: J
authors.lastname: Bian
authors.forename: Kathleen C F
authors.initials: KC
authors.lastname: Sheehan
authors.forename: James F
authors.initials: JF
authors.lastname: Zachary
authors.forename: John H
authors.initials: JH
authors.lastname: Weis
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
authors.forename: Janis J
authors.initials: JJ
authors.lastname: Weis
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D025065:Borrelia burgdorferi / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D007113:Immunity, Innate / Q000235:genetics; D007370:Interferon Type I / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D008193:Lyme Disease / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology* / Q000628:therapy; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta