Category: Autoimmune rheumatologic diseases
Background: Enthesis-resident CD4-CD8- DN T cells have been implicated in the pathogenesis of spondyloarthritis. Overexpression of IL-23 in adult mice is thought to activate these cells to produce IL-17A and other pathogenic cytokines leading to spondyloarthritis-like disease. Many innate lymphocytes require IL-1 for IL-23-induced production of IL-17A in vitro. We therefore investigated the role of IL-1 receptor signals on CD4-CD8- DN T cell homeostasis and induction of murine spondyloarthritis.
Methods: Lymphocytes were isolated from the spleen and Achilles enthesis of WT, Il23r-/-, Il1r1-/- and Il23r-gfp reporter mice (C57BL/6 background) and analyzed in vitro. Spondyloarthritis was induced by hydrodynamic injection of IL-23 minicircles in B10.RIII mice. IL-1 signals were blocked in vivo using a cocktail of three monoclonal antibodies against IL-1α, IL-1β and IL-1R1.
Results: Enthesial CD4-CD8- DN T cells comprise γδ T cells and DN αβ T cells. Both subsets secreted IL-17A in vitro upon stimulation with IL-23 + IL-1β but not IL-23 alone. Cell frequencies were not substantially different in Il23r-/- or Il1r1-/- mice compared with WT mice. Disease induction in Il1r1-/- mice could not be tested as C57BL/6 WT mice did not develop arthritis upon IL-23 minicircle injection. Antibody blockade of IL-1 in susceptible B10.RIII mice had no impact on disease onset but diminished arthritis severity.
Conclusions: C57BL/6 mice do not develop IL-23 minicircle-induced spondyloarthritis, which diniminshes the utility of this model for pathogenesis studies. Mediators other than IL-1 may provide a second signal for IL-23-induced secretion of IL-17A in vivo.