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Cited by 42Vector-borne infectious diseasesMicroRNA in disease regulationImmune Response and Inflammation

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

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Lochhead, Robert B., Ma, Ying, Zachary, James F., Baltimore, David, Zhao, Jimmy L., Weis, John H., O'Connell, Ryan M., Weis, Janis J.·2014·PLoS Pathogens
DOI 10.1371/journal.ppat.1004212PMC PMC4072785
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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.

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  • Borrelia burgdorferi infection upregulates miR-146a in murine joint tissue, suppressing IRAK1 and TRAF6.

    “Lochhead et al. reported that Borrelia burgdorferi infection leads to upregulation of miR-146a in murine joint tissue (suppressing IRAK1 and TRAF6, as mentioned before).”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [150]

    The Abstract reports miR-146a upregulation in joint tissue from three mouse strains infected with B. burgdorferi. The Results section on bone marrow-derived macrophages supports miR-146a-mediated repression of TRAF6, but reports similar IRAK1 protein levels with and without miR-146a; it does not establish suppression of both proteins in joint tissue. No page numbers are available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • miR-146a expression does not affect bacterial number in tissue, but macrophage uptake of B. burgdorferi is higher in miR-146a knockout.

    “expression of miR-146a does not affect the number of bacteria in the tissue, whereas macrophage uptake of B. burgdorferi is higher in the case of miR-146a knock-out.”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [150]

    The Results section on phagocytic activity reports greater association with B. burgdorferi in miR-146a-knockout macrophages, supporting the uptake claim. But the Results section on host defense reports fewer bacteria in infected knockout joints, although burdens in heart and ear tissue were similar. The claim that tissue bacterial numbers are unaffected is therefore too broad. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Lack of miR-146a impairs resolution of inflammation and leads to joint damage.

    “Overall, the lack of miR-146a impairs resolution of inflammation and leads to joint damage [150].”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [150]

  • Lack of miR-146a results in overactivation of NF-κB, increased myeloid cell recruitment, and more severe Lyme arthritis, but does not affect Lyme carditis.

    “Lack of miR-146a results in overactivation of NF-κB, increase in myeloid cell recruitment and more severe Lyme arthritis, whereas it does not affect Lyme carditis.”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [150]

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Cited by

Sorted by citations

Authors
Lochhead, R. B., Ma, Y., Zachary, J. F., Baltimore, D., Zhao, J. L., Weis, J. H., O'Connell, R. M., & Weis, J. J.
Affiliations
  • University of Utah (US)
  • University of Illinois Urbana-Champaign (US)
  • California Institute of Technology (US)
Corresponding author
Weis, Janis J.
ORCID
Venue
PLoS Pathogens
Publisher
Public Library of Science (PLoS)
Published
2014-06-26
Volume
10
Issue
6
Pages
e1004212
ISSN
  • 1553-7366 (ISSN-L)
  • 1553-7374
DOI
10.1371/journal.ppat.1004212
PMC
PMC4072785
OpenAlex
W2000931416
Cited by
42
References
1
Citations by year
2024: 3 · 2023: 7 · 2022: 2 · 2021: 3 · 2020: 5 · 2019: 1 · 2018: 5 · 2017: 4 · 2016: 1 · 2015: 9 · 2014: 2
FWCI
3.89
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Pathogens (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • American Cancer Society
  • University of Utah
  • National Institutes of Health (AI32223)
  • University of California, Davis
  • National Heart, Lung, and Blood Institute (R00HL102228)
  • National Institute of General Medical Sciences (DP2GM111099)
  • National Institute of Allergy and Infectious Diseases (R01 AI32223, AI055434, AI-32223, R01 AI079243A, R01AI032223, R01AI079243, T32AI055434)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR043521, R01 AR43521)
Topics
  • Life Sciences › Immunology and Microbiology › Parasitology › Vector-borne infectious diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
microRNA-146a, Lyme arthritis, Borrelia burgdorferi, Lyme carditis, NF-κB signaling, TRAF6, myeloid cell infiltration, macrophages, IL-1β, interleukin-6, CXCL1, phagocytosis, host immune response
MeSH terms
Animals, Arthritis, Infectious, Gene Expression Regulation, Inflammation, Lyme Disease, Macrophages, Mice, Inbred C3H, Mice, Inbred C57BL, Myocarditis, Phagocytosis, Signal Transduction, Interleukin-6, NF-kappa B, Interleukin-10, Mice, Knockout, Inflammation Mediators, Borrelia burgdorferi, MicroRNAs, TNF Receptor-Associated Factor 6, Mice, Interleukin-1beta, Chemokine CXCL1

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