Lyme Disease is caused by infection with the spirochete Borrelia burgdorferi, and is the most common vector-borne disease in the United States. Often, infection leads to acute arthritis in humans. Our lab and others have exploited the mouse model system to elucidate the mechanical mechanisms of Lyme Disease development. Because miRNAs have been shown to be important regulators of inflammatory and immune responses, we performed a microarray screen for expression of miRNAs in joint tissue from three infected mouse strains. This screen identified upregulation of miR-146a, a key negative regulator of NF-κB signaling. Others and we have previously demonstrated that Toll-like receptor 2/MyD88 dependent activation of NF-κB is a major regulator of immune response in mice and humans, but determining its role in arthritis development has remained elusive. We show that miR-146a plays a critical nonreduntant role in modulating Borrelia-induced NF- κB response to infection, and mice lacking this miRNA develop more severe arthritis without compromising immune response. Furthermore, miR-146a-/- mice have elevated transcript levels of NF-κB-regulated cytokines and chemokines in joint tissue, as well as increased myeloid cell infiltration, linking NF-κB dysregulation to arthritis development. Together, these data show that miR-146a is required for suppression of Lyme Arthritis, and provides a much-needed model for studying the role of NF-κB activation in arthritis development.
- Copyright © 2013 by The American Association of Immunologists, Inc.