| Description |
Lyme arthritis is the result of dysregulated immune response to infection by Borrelia burgdorferi, a tick-borne spirochete. Several immune modulators have been shown to be important to host defense and Lyme arthritis susceptibility, including toll- like receptor signaling, NF-kB activation, and various cytokines and chemokines, including type I IFN. Here we show that type I IFN and microRNAs play critical roles in modulating Lyme arthritis development. C3H mice exhibit an early, preclinical upregulation of type I IFN-responsive genes, which is associated with increased arthritis severity. Using C3H IFNAR -/- knockout mice, we showed that C3H mice lacking type I IFN signaling have a partial reduction in arthritis severity. Radiation chimeras showed that IFN signaling in both radiation sensitive and radiation resistant cells within the joint are required for maximal arthritis. Ex vivo cell sorting of cells isolated from joint tissue also showed that hematopoietic cells were the only cell types capable of initiating a type I IFN response after stimulation with B. burgdorferi, but both hematopoietic and resident cells were involved in amplification of the type I IFN response. Endothelial cells and fibroblasts were also major producers of IFN-responsive genes and inflammatory cytokines. MicroRNAs have been shown to be important immune regulators, and have been associated with several inflammatory diseases, including rheumatoid arthritis and lupus. Here we show that several microRNAs were differentially expressed in B6, C3H, and B6 IL10-/- mice infected with B. burgdorferi. MicroRNA-146a, a repressor of TLR signaling and NF-κB activation, was upregulated in all three strains, suggesting it plays an important role in the immune response to infection. B6 miR-146a-/- mice infected with B. burgdorferi developed more severe arthritis, had elevated myeloid infiltration, upregulation of inflammatory cytokines, and had fewer numbers of bacteria in joint tissue at 4 weeks postinfection, indicating that miR-146a-mediated regulation of NF-κB activation modulated immune response and arthritis development. Similar patterns of dysregulation were observed in B6 miR-146a -/- macrophages, which produced excessive cytokines, exhibited increased phagocytosis, and had elevated protein levels of TRAF6. Together, these data show that miR-146a is a critical regulator of NF-κB activation and arthritis development during infection with B. burgdorferi. |
