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      MicroRNA-146a Provides Feedback Regulation of Lyme Arthritis but Not Carditis during Infection with Borrelia burgdorferi

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          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.

          Author Summary

          Lyme Disease is caused by infection with the bacteria Borrelia burgdorferi, is transmitted through infected deer ticks ( Ixodes scapularis), and often leads to arthritis that can persist, even after antibiotic treatment. Here, we have identified a microRNA that is critical in modulating Lyme arthritis, but not carditis. This microRNA, miR-146a, is a negative regulator of NF-κB signaling, known to be important in host defense against pathogens, and long suspected to play a role in Lyme arthritis development. Mice lacking miR-146a develop more severe arthritis and show signs of hyperactive NF-κB activation during the persistent phase of infection. Heart manifestations of disease were not altered. Furthermore, this severe arthritis is independent of host defense, since these mice are better able to clear invading bacteria in joints, and bacterial numbers are similar in heart and ear tissue. We identified TRAF6 as an important target of miR-146a-mediated NF-κB regulation of pro-inflammatory cytokines IL-6 and IL-1β, as well as chemokines CXCL1 and CXCL2. Our data demonstrate the importance of maintaining appropriate regulation of amplitude and resolution of NF-κB activation during Borrelia burgdorferi infection, and provide a novel model for elucidating the role of NF-κB in Lyme arthritis development, independent of effect on host defense.

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          Most cited references82

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          MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development.

          Mammalian noncoding microRNAs (miRNAs) are a class of gene regulators that have been linked to immune system function. Here, we have investigated the role of miR-155 during an autoimmune inflammatory disease. Consistent with a positive role for miR-155 in mediating inflammatory responses, Mir155(-/-) mice were highly resistant to experimental autoimmune encephalomyelitis (EAE). miR-155 functions in the hematopoietic compartment to promote the development of inflammatory T cells including the T helper 17 (Th17) cell and Th1 cell subsets. Furthermore, the major contribution of miR-155 to EAE was CD4(+) T cell intrinsic, whereas miR-155 was also required for optimum dendritic cell production of cytokines that promoted Th17 cell formation. Our study shows that one aspect of miR-155 function is the promotion of T cell-dependent tissue inflammation, suggesting that miR-155 might be a promising therapeutic target for the treatment of autoimmune disorders. Copyright © 2010 Elsevier Inc. All rights reserved.
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            Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis.

            MicroRNAs (miRNA) have recently emerged as a new class of modulators of gene expression. In this study we investigated the expression, regulation, and function of miR-155 and miR-146a in rheumatoid arthritis (RA) synovial fibroblasts (RASFs) and RA synovial tissue. Locked nucleic acid microarray was used to screen for differentially expressed miRNA in RASFs treated with tumor necrosis factor alpha (TNFalpha). TaqMan-based real-time polymerase chain reaction was applied to measure the levels of miR-155 and miR-146a. Enforced overexpression of miR-155 was used to investigate the function of miR-155 in RASFs. Microarray analysis of miRNA expressed in RASFs treated with TNFalpha revealed a prominent up-regulation of miR-155. Constitutive expression of both miR-155 and miR-146a was higher in RASFs than in those from patients with osteoarthritis (OA), and expression of miR-155 could be further induced by TNFalpha, interleukin-1beta, lipopolysaccharide, poly(I-C), and bacterial lipoprotein. The expression of miR-155 in RA synovial tissue was higher than in OA synovial tissue. Enforced expression of miR-155 in RASFs was found to repress the levels of matrix metalloproteinase 3 (MMP-3) and reduce the induction of MMPs 3 and 1 by Toll-like receptor ligands and cytokines. Moreover, compared with monocytes from RA peripheral blood, RA synovial fluid monocytes displayed higher levels of miR-155. This study provides the first description of increased expression of miRNA miR-155 and miR-146a in RA. Based on these findings, we postulate that the inflammatory milieu may alter miRNA expression profiles in resident cells of the rheumatoid joints. Considering the repressive effect of miR-155 on the expression of MMPs 3 and 1 in RASFs, we hypothesize that miR-155 may be involved in modulation of the destructive properties of RASFs.
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              The long and short of microRNA.

              MicroRNAs (miRNAs) are versatile regulators of gene expression in higher eukaryotes. In order to silence many different mRNAs in a precise manner, miRNA stability and efficacy is controlled by highly developed regulatory pathways and fine-tuning mechanisms both affecting miRNA processing and altering mature miRNA target specificity. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                June 2014
                26 June 2014
                : 10
                : 6
                : e1004212
                Affiliations
                [1 ]Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America
                [2 ]Department of Veterinary Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
                [3 ]Department of Biology, California Institute of Technology, Pasadena, California, United States of America
                Medical College of Wisconsin, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: RBL JHW RMOC JJW. Performed the experiments: RBL YM. Analyzed the data: RBL JFZ JJW. Contributed reagents/materials/analysis tools: DB JLZ JJW. Wrote the paper: RBL JJW.

                Article
                PPATHOGENS-D-13-02792
                10.1371/journal.ppat.1004212
                4072785
                24967703
                1f293873-9ffe-43c9-91a4-a7e00113a34e
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 24 October 2013
                : 13 May 2014
                Page count
                Pages: 20
                Funding
                RBL was supported by a National Institute of Allergy and Infectious Diseases Research Training Grant (T32 AI055434). DB was supported by a National Institutes of Health Award (R01 AI079243A). RMOC was supported by a NIH New Innovator Award (DP2GM111099-01), a National Heart, Lung, and Blood Institute Career Development Award (R00HL102228-05), and an American Cancer Society Research Grant. JJW was supported by NIH Awards (R01 AI32223 and R01 AR43521). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases, the National Heart, Lung, and Blood Institute, the American Cancer Society, or the National Institutes of Health.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                White Blood Cells
                Monocytes
                Immune Cells
                Genetics
                Gene Expression
                Gene Regulation
                Molecular Genetics
                Immunology
                Clinical Immunology
                Immunomodulation
                Immune Response
                Inflammation
                Immune System
                Innate Immune System
                Immunity
                Immune Activation
                Immunoregulation
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Bacterial Pathogens
                Medicine and Health Sciences
                Infectious Diseases
                Bacterial Diseases
                Borrelia Infection
                Emerging Infectious Diseases
                Pathology and Laboratory Medicine
                Pathogenesis
                Host-Pathogen Interactions
                Research and Analysis Methods
                Model Organisms
                Animal Models
                Mouse Models

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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