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Cited by 158Tuberculosis Research and EpidemiologyImmune cells in cancerMicroRNA in disease regulation

MicroRNA 26a (miR-26a)/KLF4 and CREB-C/EBPβ regulate innate immune signaling, the polarization of macrophages and the trafficking of Mycobacterium tuberculosis to lysosomes during infection

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Sahu, Sanjaya Kumar, Kumar, Manish, Chakraborty, Sohini, Banerjee, Srijon Kaushik, Kumar, Ranjeet, Gupta, Pushpa, Jana, Kuladip, Gupta, Umesh D. +3 more·2017·PLOS Pathogens
DOI 10.1371/journal.ppat.1006410PMC PMC5466338
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Abstract

For efficient clearance of Mycobacterium tuberculosis (Mtb), macrophages tilt towards M1 polarization leading to the activation of transcription factors associated with the production of antibacterial effector molecules such as nitric oxide (NO) and proinflammatory cytokines such as interleukin 1 β (IL-1β) and tumor necrosis factor α (TNF-α). At the same time, resolution of inflammation is associated with M2 polarization with increased production of arginase and cytokines such as IL-10. The transcriptional and post-transcriptional mechanisms that govern the balance between M1 and M2 polarization, and bacteria-containing processes such as autophagy and trafficking of Mtb to lysosomes, are incompletely understood. Here we report for the first time, that the transcription factor KLF4 is targeted by microRNA-26a (miR-26a). During Mtb infection, downregulation of miR-26a (observed both ex vivo and in vivo) facilitates upregulation of KLF4 which in turn favors increased arginase and decreased iNOS activity. We further demonstrate that KLF4 prevents trafficking of Mtb to lysosomes. The CREB-C/EBPβ signaling axis also favors M2 polarization. Downregulation of miR-26a and upregulation of C/ebpbeta were observed both in infected macrophages as well as in infected mice. Knockdown of C/ebpbeta repressed the expression of selected M2 markers such as Il10 and Irf4 in infected macrophages. The importance of these pathways is substantiated by observations that expression of miR-26a mimic or knockdown of Klf4 or Creb or C/ebpbeta, attenuated the survival of Mtb in macrophages. Taken together, our results attribute crucial roles for the miR-26a/KLF4 and CREB-C/EBPβsignaling pathways in regulating the survival of Mtb in macrophages. These studies expand our understanding of how Mtb hijacks host signaling pathways to survive in macrophages, and open up new exploratory avenues for host-targeted interventions.

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  • miR-26a regulates the CREB-C/EBPβ signaling axis, and its downregulation in Mycobacterium tuberculosis infection favors M2 polarization.

    “MiR-26a also regulates the CREB-C/EBPβ signaling axis, and its downregulation in Mycobacterium tuberculosis (Mtb) infection favors M2 polarization [126].”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [126]

    The Introduction and Results report that miR-26a falls during Mtb infection and that its downregulation increases KLF4, favoring M2 polarization. They describe CREB–C/EBPβ as another pathway that favors M2 polarization, not as an axis regulated by miR-26a. Page numbers are unavailable in our copy. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Mtb infection downregulates miR-26a, derepressing KLF4, impairing Mtb trafficking to lysosomes, and contributing to Mtb survival.

    “Mtb infection leads to downregulation of miR-26a and subsequent derepression of KLF4, which further impairs trafficking of Mtb to lysosomes, thus contributing to Mtb survival [126].”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [126]

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Authors
Sahu, S. K., Kumar, M., Chakraborty, S., Banerjee, S. K., Kumar, R., Gupta, P., Jana, K., Gupta, U. D., Ghosh, Z., Kundu, M., & Basu, J.
Affiliations
  • Bose Institute (IN)
  • National JALMA Institute for Leprosy & Other Mycobacterial Diseases (IN)
Corresponding author
Basu, Joyoti
ORCID
Venue
PLOS Pathogens
Publisher
Public Library of Science (PLoS)
Published
2017-05-30
Volume
13
Issue
5
Pages
e1006410
ISSN
  • 1553-7366 (ISSN-L)
  • 1553-7374
DOI
10.1371/journal.ppat.1006410
PMC
PMC5466338
OpenAlex
W2617196371
Cited by
158
References
7
Citations by year
2026: 8 · 2025: 12 · 2024: 10 · 2023: 13 · 2022: 21 · 2021: 24 · 2020: 25 · 2019: 23 · 2018: 18 · 2017: 3
FWCI
14.53
Type
journal article
Language
en
Update notices
new_version (2017-06-09)
Open access
Licence
Locations
  • PLoS Pathogens (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DiVA at Umeå University (Umeå University) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Department of Biotechnology, Ministry of Science and Technology (BT/PR3260/BRB/10/967/2011)
  • Council of Scientific and Industrial Research (19-12/2010(i)EU-IV)
  • University Grants Commission, Government of India (20-6/2009(i)EU-IV)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
Keywords
Mycobacterium tuberculosis, miR-26a, KLF4, macrophage polarization, M1/M2 macrophages, innate immune signaling, lysosomal trafficking, autophagy, arginase, inducible nitric oxide synthase, IL-10, IRF4, host-pathogen interaction, tuberculosis
MeSH terms
RAW 264.7 Cells, Kruppel-Like Factor 4, Animals, Humans, Lysosomes, Macrophages, Mycobacterium tuberculosis, Tuberculosis, Signal Transduction, Cell Polarity, CCAAT-Enhancer-Binding Protein-beta, MicroRNAs, CREB-Binding Protein, Mice, Kruppel-Like Transcription Factors

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