title: Endothelial cells and fibroblasts amplify the arthritogenic type I IFN response in murine Lyme disease and are major sources of chemokines in Borrelia burgdorferi-infected joint tissue.
abstract: Localized elevation in type I IFN has been uniquely linked to the severe Lyme arthritis that develops in C3H mice infected with the spirochete Borrelia burgdorferi. In this study, the dynamic interactions that result in generation of these responses were further examined in C3H mice carrying the type I IFN receptor gene ablation, which effectively blocks all autocrine/paracrine signaling crucial to induction of downstream effectors. Reciprocal radiation chimeras between C3H and IFNAR1⁻/⁻ mice implicated both radiation-sensitive and radiation-resistant cells of the joint tissue in the proarthritic induction of type I IFN. Ex vivo analysis of cells from the naive joint revealed CD45⁺ cells residing in the tissue to be uniquely capable of initiating the type I IFN response to B. burgdorferi. Type I IFN responses were analyzed in real time by lineage sorting of cells from infected joint tissue. This demonstrated that myeloid cells, endothelial cells, and fibroblasts were responsible for propagating the robust IFN response, which peaked at day 7 postinfection and rapidly resolved. Endothelial cells and fibroblasts were the dominant sources of IFN signature transcripts in the joint tissue. Fibroblasts were also the major early source of chemokines associated with polymorphonuclear leukocyte and monocyte/macrophage infiltration, thus providing a focal point for arthritis development. These findings suggest joint-localized interactions among related and unrelated stromal, endothelial, and myeloid cell lineages that may be broadly applicable to understanding the pathogeneses of diseases associated with type I IFN signature, including systemic lupus erythematosus and some rheumatoid arthritides.
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Lochhead
authors.forename: F Lynn
authors.initials: FL
authors.lastname: Sonderegger
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.forename: James E
authors.initials: JE
authors.lastname: Brewster
authors.forename: Doug
authors.initials: D
authors.lastname: Cornwall
authors.forename: Heather
authors.initials: H
authors.lastname: Maylor-Hagen
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Miller
authors.forename: James F
authors.initials: JF
authors.lastname: Zachary
authors.forename: John H
authors.initials: JH
authors.lastname: Weis
authors.forename: Janis J
authors.initials: JJ
authors.lastname: Weis
mesh_terms: D000818:Animals; D000843:Ankle Joint / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D025065:Borrelia burgdorferi / Q000276:immunology / Q000472:pathogenicity; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007370:Interferon Type I / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D008193:Lyme Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000276:immunology; D014158:Transcription, Genetic / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
chemical_list: D018925:Chemokines; D007370:Interferon Type I