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Cited by 45Research on Leishmaniasis StudiesImmune cells in cancerParasitic Diseases Research and Treatment

Super enhancer-mediated transcription of miR146a-5p drives M2 polarization during Leishmania donovani infection

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Das, Sonali, Mukherjee, Sohitri, Ali, Nahid·2021·PLOS Pathogens
DOI 10.1371/journal.ppat.1009343PMC PMC7943006
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Abstract

The outcome of Leishmania donovani infection depends upon the dynamic interchanges between M1 and M2 macrophages. Information of the involvement of microRNAs (miRNAs) and epigenetic modifiers in regulating macrophage plasticity during L . donovani infection is still elusive. Differential expression analysis of polarization-regulating miRNAs, revealed significant enrichment of miR146a-5p during Leishmania donovani infection. A sustained enrichment of miR146a-5p was observed in both infected bone marrow derived macrophages (BMDMs) and BALB/c mice organs. We found involvement of miR146a-5p in phagocytosis and survivability of parasites. Moreover, miR146a-5pgot enriched in interleukin 4- stimulated BMDMs, indicating its possible involvement in M2 polarization. Upon transfecting BMDMs with miRVANA anti-146a oligos, M2 markers (CCR7, YM-1, FIZZ-1, arginase-1, IL10 and IL4) and transcription factors (p-STAT6 and c/EBPβ) got depleted with concomitant augmentation of M1-polarizing transcription factors (p-STAT1, AP1 and IRF-1), miR146a target genes (TRAF6 and IRAK1), M1 cytokines (IL12 and TNFα), i NOS, nitric oxide, and nuclear translocation of phospho p-65 subunit. Neutralization of intracellular mature miR146a-5p pool in infected BALB/c mice lower organ parasite burden and expressions of M2 markers and IL10 with enrichment of M1 markers like i NOS and IL12. Additionally, we explored the novel role of super enhancer (SE), a cis-acting regulatory component, to enrich miR146a-5p expression during infection. Enhanced expression and nuclear retention of SE components like BET bromodomain 4 (BRD4) and p300 were found in infected BMDMs. Upon silencing BRD4, expressions of miR146a-5p and M2 markers were down regulated and TRAF6, IRAK1 and i NOS levels increased. STRING V.11 based predication and immune precipitation confirmed the strong interaction amongst BRD4, p300 and RNA pol II (RpbI). Chromatin immune precipitation studies suggested the recruitment of BRD4 at the enhancer loci of miR146a-5p gene during infection. Altogether, our findings revealed a novel role of BRD4/p300-depdendent super-enhancer in regulating miR146a expression during L . donovani infection which in turn mediates M2 polarization and immune-suppression.

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  • Upon Leishmania donovani infection, miR-146a-5p is upregulated in a BRD4/p300-dependent manner; miR-181a-5p and miR-125a-5p are upregulated, whereas miR-26a-5p is downregulated, which promotes M2 over M1 polarization.

    “Contrary to the abovementioned NGS results, Das et al. reported that upon Leishmania donovani infection, miR-146a-5p is upregulated in a BET bromodomain protein 4 (BRD4)/p300-depdendent manner (in this conditions miR-181a-5p and miR-125a-5p are upregulated too, whereas miR-26a-5p is downregulated, which promotes M2 over M1 polarization).”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [153]

  • Silencing of miR-146a-5p resulted in downregulation of M2 markers (YM1, FIZZ1, CCR7, Arg1, pSTAT6 and c/EBPβ) and upregulation of p-STAT1, IRF-1, AP1, TRAF6, IRAK1, which resulted in an increase in IL-12 and TNFα production.

    “They showed that silencing of miR-146a-5p resulted in downregulation of M2 markers (YM1, FIZZ1, CCR7, Arg1, pSTAT6 and c/EBPβ) and upregulation of p-STAT1, IRF-1, AP1, TRAF6, IRAK1, which resulted in an increase in IL-12 and TNFα production [153].”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [153]

  • Silencing miR-146a decreases L. donovani uptake.

    “its silencing was demonstrated to decrease L. donovani uptake [153]”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [153]

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Sorted by citations

Authors
Das, S., Mukherjee, S., & Ali, N.
Affiliations
Indian Institute of Chemical Biology (IN)
Corresponding author
Ali, Nahid
ORCID
Ali, Nahid
Venue
PLOS Pathogens
Publisher
Public Library of Science (PLoS)
Published
2021-02-25
Volume
17
Issue
2
Pages
e1009343
ISSN
  • 1553-7366 (ISSN-L)
  • 1553-7374
DOI
10.1371/journal.ppat.1009343
PMC
PMC7943006
OpenAlex
W3130089727
Cited by
45
References
6
Citations by year
2026: 4 · 2025: 10 · 2024: 7 · 2023: 12 · 2022: 8 · 2021: 4
FWCI
6.72
Type
journal article
Language
en
Update notices
new_version (2021-03-09)
Open access
Licence
Locations
  • PLoS Pathogens (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Greater South Information System
Funders
  • Global Challenges Research Fund (MR/P027989/1)
  • Sir J C Bose national fellowship (http://www.serb.gov.in/jcbn.php)
  • Council of Scientific and Industrial research (https://www.csirhrdg.res.in/)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Research on Leishmaniasis Studies
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Infectious Diseases › Parasitic Diseases Research and Treatment
Keywords
super-enhancers, M2 macrophage polarization, BRD4, P300, RNA polymerase II, TRAF6, IRAK1, IL-10, STAT6, C/EBPβ, macrophage plasticity, parasite survival, nitric oxide, epigenetic regulation
MeSH terms
Animals, Enhancer Elements, Genetic, Leishmania donovani, Leishmaniasis, Macrophages, Mice, Inbred BALB C, Phagocytosis, MicroRNAs, STAT6 Transcription Factor, Mice, Nitric Oxide Synthase Type II, Interleukin-1 Receptor-Associated Kinases

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