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MicroRNA-146a provides feedback regulation of lyme arthritis but not carditis during infection with Borrelia burgdorferi.
PLoS Pathog. 2014 Jun; 10(6):e1004212.PP

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+Show Affiliations

Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.Department of Veterinary Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.Department of Biology, California Institute of Technology, Pasadena, California, United States of America.Department of Biology, California Institute of Technology, Pasadena, California, United States of America.Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

24967703

Citation

Lochhead, Robert B., et al. "MicroRNA-146a Provides Feedback Regulation of Lyme Arthritis but Not Carditis During Infection With Borrelia Burgdorferi." PLoS Pathogens, vol. 10, no. 6, 2014, pp. e1004212.
Lochhead RB, Ma Y, Zachary JF, et al. MicroRNA-146a provides feedback regulation of lyme arthritis but not carditis during infection with Borrelia burgdorferi. PLoS Pathog. 2014;10(6):e1004212.
Lochhead, R. B., Ma, Y., Zachary, J. F., Baltimore, D., Zhao, J. L., Weis, J. H., O'Connell, R. M., & Weis, J. J. (2014). MicroRNA-146a provides feedback regulation of lyme arthritis but not carditis during infection with Borrelia burgdorferi. PLoS Pathogens, 10(6), e1004212. https://doi.org/10.1371/journal.ppat.1004212
Lochhead RB, et al. MicroRNA-146a Provides Feedback Regulation of Lyme Arthritis but Not Carditis During Infection With Borrelia Burgdorferi. PLoS Pathog. 2014;10(6):e1004212. PubMed PMID: 24967703.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MicroRNA-146a provides feedback regulation of lyme arthritis but not carditis during infection with Borrelia burgdorferi. AU - Lochhead,Robert B, AU - Ma,Ying, AU - Zachary,James F, AU - Baltimore,David, AU - Zhao,Jimmy L, AU - Weis,John H, AU - O'Connell,Ryan M, AU - Weis,Janis J, Y1 - 2014/06/26/ PY - 2013/10/24/received PY - 2014/05/13/accepted PY - 2014/6/27/entrez PY - 2014/6/27/pubmed PY - 2015/9/1/medline SP - e1004212 EP - e1004212 JF - PLoS pathogens JO - PLoS Pathog. VL - 10 IS - 6 N2 - 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. SN - 1553-7374 UR - https://www.unboundmedicine.com/medline/citation/24967703/MicroRNA_146a_provides_feedback_regulation_of_lyme_arthritis_but_not_carditis_during_infection_with_Borrelia_burgdorferi_ L2 - http://dx.plos.org/10.1371/journal.ppat.1004212 DB - PRIME DP - Unbound Medicine ER -