title: MicroRNA-146a provides feedback regulation of lyme arthritis but not carditis during infection with Borrelia burgdorferi.
abstract: MicroRNAs have been shown to be important regulators of inflammatory and immune responses and are implicated in several immune disorders including systemic lupus erythematosus and rheumatoid arthritis, but their role in Lyme borreliosis remains unknown. We performed a microarray screen for expression of miRNAs in joint tissue from three mouse strains infected with Borrelia burgdorferi. This screen identified upregulation of miR-146a, a key negative regulator of NF-κB signaling, in all three strains, suggesting it plays an important role in the in vivo response to B. burgdorferi. Infection of B6 miR-146a-/- mice with B. burgdorferi revealed a critical nonredundant role of miR-146a in modulating Lyme arthritis without compromising host immune response or heart inflammation. The impact of miR-146a was specifically localized to the joint, and did not impact lesion development or inflammation in the heart. Furthermore, B6 miR-146a-/- mice had elevated levels of NF-κB-regulated products in joint tissue and serum late in infection. Flow cytometry analysis of various lineages isolated from infected joint tissue of mice showed that myeloid cell infiltration was significantly greater in B6 miR-146a-/- mice, compared to B6, during B. burgdorferi infection. Using bone marrow-derived macrophages, we found that TRAF6, a known target of miR-146a involved in NF-κB activation, was dysregulated in resting and B. burgdorferi-stimulated B6 miR-146a-/- macrophages, and corresponded to elevated IL-1β, IL-6 and CXCL1 production. This dysregulated protein production was also observed in macrophages treated with IL-10 prior to B. burgdorferi stimulation. Peritoneal macrophages from B6 miR-146a-/- mice also showed enhanced phagocytosis of B. burgdorferi. Together, these data show that miR-146a-mediated regulation of TRAF6 and NF-κB, and downstream targets such as IL-1β, IL-6 and CXCL1, are critical for modulation of Lyme arthritis during chronic infection with B. burgdorferi.
authors: Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.
authors: Robert B
authors: RB
authors: Lochhead
authors: Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.
authors: Ying
authors: Y
authors: Ma
authors: Department of Veterinary Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
authors: James F
authors: JF
authors: Zachary
authors: Department of Biology, California Institute of Technology, Pasadena, California, United States of America.
authors: David
authors: D
authors: Baltimore
authors: Department of Biology, California Institute of Technology, Pasadena, California, United States of America.
authors: Jimmy L
authors: JL
authors: Zhao
authors: Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.
authors: John H
authors: JH
authors: Weis
authors: Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.
authors: Ryan M
authors: RM
authors: O'Connell
authors: Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.
authors: Janis J
authors: JJ
authors: Weis
mesh_terms: D000818:Animals; D001170:Arthritis, Infectious / Q000235:genetics* / Q000382:microbiology; D025065:Borrelia burgdorferi / Q000276:immunology* / Q000472:pathogenicity; D054360:Chemokine CXCL1 / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics; D007249:Inflammation / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008193:Lyme Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D009205:Myocarditis / Q000235:genetics* / Q000382:microbiology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D048029:TNF Receptor-Associated Factor 6 / Q000096:biosynthesis / Q000276:immunology
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; C556062:IL10 protein, mouse; C587672:IL1B protein, mouse; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D016753:Interleukin-10