Welcome to the new version of CaltechAUTHORS. Login is currently restricted to library staff. If you notice any issues, please email coda@library.caltech.edu
Published June 2014 | Supplemental Material + Published
Journal Article Open

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.

Additional Information

Copyright: © 2014 Lochhead et al. 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. Received: October 24, 2013; Accepted: May 13, 2014; Published: June 26, 2014. We would like to acknowledge Lynn Sonderegger, Kenneth Bramwell, Betsy Ott Crowther, Jackie Engel Paquette and Sarah Whiteside for their technical assistance, training, advice and manuscript review; as well as Brian Dalley (Microarray), David Nix (Bioinformatics), Chris Leukel (Flow Cytometry) and Chris Rodesh (Cell Imaging) from the University of Utah Core Facilities for their expertise and assistance. 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.

Attached Files

Published - journal.ppat.1004212.pdf

Supplemental Material - journal.ppat.1004212.s001.tif

Supplemental Material - journal.ppat.1004212.s002.tif

Supplemental Material - journal.ppat.1004212.s003.xlsx

Files

journal.ppat.1004212.pdf
Files (11.5 MB)
Name Size Download all
md5:1b854e4088360aedfe831b7458382fe2
8.9 MB Preview Download
md5:f74a81adc1c68a93103e944b798f821b
53.9 kB Download
md5:53f348d08a3e22122633a3068a062def
2.3 MB Preview Download
md5:dc8fe31e073ea7bc9eab3815c08e7254
265.8 kB Preview Download

Additional details

Created:
August 20, 2023
Modified:
October 26, 2023