title: Localized production of IL-10 suppresses early inflammatory cell infiltration and subsequent development of IFN-γ-mediated Lyme arthritis.
abstract: IL-10 is a nonredundant inflammatory modulator that suppresses arthritis development in Borrelia burgdorferi-infected mice. Infected C57BL/6 (B6) IL-10(-/-) mice were previously found to have a prolonged IFN-inducible response in joint tissue. Infection of B6 IL-10 reporter mice identified macrophages and CD4(+) T cells as the primary sources of IL-10 in the infected joint tissue, suggesting that early local production of IL-10 dampened the proarthritic IFN response. Treatment of B6 IL-10(-/-) mice with anti-IFN-γ reduced the increase in arthritis severity and suppressed IFN-inducible transcripts to wild-type levels, thereby linking dysregulation of IFN-γ to disease in the B6 IL-10(-/-) mouse. Arthritis in B6 IL-10(-/-) mice was associated with elevated numbers of NK cell, NKT cell, α/β T cell, and macrophage infiltration of the infected joint. FACS lineage sorting revealed NK cells and CD4(+) T cells as sources of IFN-γ in the joint tissue of B6 IL-10(-/-) mice. These findings suggest the presence of a positive-feedback loop in the joint tissue of infected B6 IL-10(-/-) mice, in which production of inflammatory chemokines, infiltration of IFN-γ-producing cells, and additional production of inflammatory cytokines result in arthritis. This mechanism of arthritis is in contrast to that seen in C3H/He mice, in which arthritis development is linked to transient production of type I IFN and develops independently of IFN-γ. Due to the sustained IFN response driven by NK cells and T cells, we propose the B6 IL-10(-/-) mouse as a potential model to study the persistent arthritis observed in some human Lyme disease patients.
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: F Lynn
authors.initials: FL
authors.lastname: Sonderegger
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.forename: Heather
authors.initials: H
authors.lastname: Maylor-Hagan
authors.forename: James
authors.initials: J
authors.lastname: Brewster
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Huang
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Spangrude
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; D025065:Borrelia burgdorferi; D002465:Cell Movement / Q000276:immunology*; D025461:Feedback, Physiological; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000172:deficiency; D007694:Killer Cells, Natural / Q000276:immunology; D008193:Lyme Disease / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: C556062:IL10 protein, mouse; D016753:Interleukin-10; D007371:Interferon-gamma