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Tannic acid prevents macrophage-induced pro-fibrotic response in lung epithelial cells via suppressing TLR4-mediated macrophage polarization

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Abstract

Background

Polarized macrophages induce fibrosis through multiple mechanisms, including a process termed epithelial-to-mesenchymal transition (EMT). Mesenchymal cells contribute to the excessive accumulation of fibrous connective tissues, leading to organ failure. This study was aimed to investigate the effect of tannic acid (TA), a natural dietary polyphenol on M1 macrophage-induced EMT and its underlying mechanisms.

Materials

First, we induced M1 polarization in macrophage cell lines (RAW 264.7 and THP-1). Then, the conditioned-medium (CM) from these polarized macrophages was used to induce EMT in the human adenocarcinomic alveolar epithelial (A549) cells. We also analysed the role of TA on macrophage polarization.

Results

We found that TA pre-treated CM did not induce EMT in epithelial cells. Further, TA pre-treated CM showed diminished activation of MAPK in epithelial cells. Subsequently, TA was shown to inhibit LPS-induced M1 polarization in macrophages by directly targeting toll-like receptor 4 (TLR4), thereby repressing LPS binding to TLR4/MD2 complex and subsequent signal transduction.

Conclusion

It was concluded that TA prevented M1 macrophage-induced EMT by suppressing the macrophage polarization possibly through inhibiting the formation of LPS-TLR4/MD2 complex and blockage of subsequent downstream signal activation. Further, our findings may provide beneficial information to develop new therapeutic strategies against chronic inflammatory diseases.

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Acknowledgements

This work was supported by Ramalingaswami re-entry fellowship (BT/RLF/Re-entry/36/2013). S. R. is the recipient of Ramalingaswami re-entry fellowship from the Department of Biotechnology (DBT), Government of India. This study was also supported in part by the Department of Science and Technology (DST; Award No: YSS/2014/000125) (to S. R.), Government of India. The first author (A. S.) gratefully acknowledges the support of Indian Council of Medical Research (ICMR), New Delhi, India for the award of ICMR‐Senior Research Fellowship (SRF; Award No: 45/03/2018‐BMS/PHA/OL). The infrastructure of Department of Biotechnology, Anna University, BIT-campus is supported by the Department of Science and Technology-Fund for Improvement of S and T Infrastructure in Universities and Higher Educational Institutions (DST-FIST).

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Authors and Affiliations

  1. Department of Biotechnology, BIT-Campus, Anna University, Tiruchirappalli, Tamil Nadu, India

    Ayyanar Sivanantham, Dhamotharan Pattarayan, Nandhine Rajasekar, Rajaguru Palanichamy & Subbiah Rajasekaran

  2. Centre for Research in Infectious Diseases (CRID), School of Chemical and Biotechnology, SASTRA Deemed To Be University, Thanjavur, Tamil Nadu, India

    Adithi Kannan & Santanu Kar Mahapatra

  3. Pharmacogenomics and CADD Lab, Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu, India

    Lakshmanan Loganathan & Karthikeyan Muthusamy

  4. Department of Immunology, ICMR-National Institute for Research in Tuberculosis, Chennai, Tamil Nadu, India

    Ramalingam Bethunaickan

  5. Department of Biochemistry, ICMR-National Institute for Research in Environmental Health, Kamla Nehru Hospital Building, Gandhi Medical College Campus, Bhopal, Madhya Pradesh, India

    Subbiah Rajasekaran

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  1. Ayyanar Sivanantham
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  2. Dhamotharan Pattarayan
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  5. Lakshmanan Loganathan
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  8. Rajaguru Palanichamy
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Contributions

SR has conceptualized, designed the experiments, acquired financial support, supervised the study, and wrote the manuscript; AS performed most of the experiments; DP and NR involved in the acquisition of data; AS, DP and SR analysed data and interpreted the results; AK and SKM participated in cytokine analysis; LL and KM participated in computational analysis; RB participated in flow cytometry analysis; RB, SKM and RP contributed reagents/materials/analysis tools.

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Correspondence to Subbiah Rajasekaran.

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Sivanantham, A., Pattarayan, D., Rajasekar, N. et al. Tannic acid prevents macrophage-induced pro-fibrotic response in lung epithelial cells via suppressing TLR4-mediated macrophage polarization. Inflamm. Res. 68, 1011–1024 (2019). https://doi.org/10.1007/s00011-019-01282-4

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  • DOI: https://doi.org/10.1007/s00011-019-01282-4

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