MicroRNA 21 Elicits a Pro-inflammatory Response in Macrophages, with Exosomes Functioning as Delivery Vehicles
Abstract
MicroRNAs can regulate inflammatory responses by modulating macrophage polarization. Although microRNA miR-21 is linked to crucial processes involved in inflammatory responses, its precise role in macrophage polarization is controversial. In this study, we investigated the functional relevance of endogenous miRNA-21 and the role of exosomes. RAW 264.7 macrophages were transfected with miR-21 plasmid, and the inflammatory response was evaluated by flow cytometry, phagocytosis, and real-time PCR analysis of inflammatory cytokines. To understand the signaling pathways' role, the cells were treated with inhibitors specific for PI3K or NFĸB. Exosomes from transfected cells were used to study the paracrine action of miR-21 on naive macrophages. Overexpression of miR-21 resulted in significant upregulation of pro-inflammatory cytokines, pushing the cells towards a pro-inflammatory phenotype, with partial involvement of PI3K and NFĸB signal pathways. The cells also secreted miR-21 rich exosomes, which, on delivery to naive macrophages, caused them to exhibit pro-inflammatory activity. The presence of miR-21 inhibitor quenched the inflammatory response. This study validates the pro-inflammatory property of miR-21 with a tendency to foster an inflammatory milieu. Our findings also reinforce the dual importance of exosomal miR-21 as a biomarker and therapeutic target in inflammatory conditions.
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In stressed Ast-AD, only miR-21 was found enriched in their derived exosomes.
“In this condition, only miR-21 was found to be enriched in their derived exosomes and may further elicit a pro-inflammatory response [123].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [123]
Macrophages secrete miR-21-containing exosomes, spreading the reaction to other macrophages, mainly through polarization towards the pro-inflammatory phenotype, as in the case of miR-27a.
“Macrophages are capable of secreting miR-21-containing exosomes, thus spreading the reaction to other macrophages [117], mainly through polarization towards the pro-inflammatory phenotype [128] as in the case of miR-27a.”
From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [117]
Cites
NF-κB signaling in inflammation
Liu, T., Zhang, L., Joo, D., & Sun, S.-C. (2017) · Signal Transduction and Targeted Therapy · doi:10.1038/sigtrans.2017.23 · Cited by 8,791 · see citing works
Isolation and Characterization of Exosomes from Cell Culture Supernatants and Biological Fluids
Théry, C., Amigorena, S., Raposo, G., & Clayton, A. (2006) · Current Protocols in Cell Biology · doi:10.1002/0471143030.cb0322s30 · Cited by 5,766 · see citing works
Protective and pathogenic functions of macrophage subsets
Murray, P. J., & Wynn, T. A. (2011) · Nature Reviews Immunology · doi:10.1038/nri3073 · Cited by 5,269 · see citing works
Doyle, L. M., & Wang, M. Z. (2019) · Cells · doi:10.3390/cells8070727 · Cited by 3,271 · see citing works
Diversity, Mechanisms, and Significance of Macrophage Plasticity
Locati, M., Curtale, G., & Mantovani, A. (2020) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-012418-012718 · Cited by 2,199 · see citing works
Secretory Mechanisms and Intercellular Transfer of MicroRNAs in Living Cells
Kosaka, N., Iguchi, H., Yoshioka, Y., Takeshita, F., Matsuki, Y., & Ochiya, T. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.107821 · Cited by 1,934 · see citing works
Inflammation and wound healing: the role of the macrophage
Koh, T. J., & DiPietro, L. A. (2011) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399411001943 · Cited by 1,667 · see citing works
microRNA Regulation of Inflammatory Responses
O’Connell, R. M., Rao, D. S., & Baltimore, D. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-075013 · Cited by 957 · see citing works
Harrell, C. R., Jovicic, N., Djonov, V., Arsenijevic, N., & Volarevic, V. (2019) · Cells · doi:10.3390/cells8121605 · Cited by 795 · see citing works
Exosome-delivered microRNAs modulate the inflammatory response to endotoxin
Alexander, M., Hu, R., Runtsch, M. C., Kagele, D. A., Mosbruger, T. L., Tolmachova, T., Seabra, M. C., Round, J. L., Ward, D. M., & O’Connell, R. M. (2015) · Nature Communications · doi:10.1038/ncomms8321 · Cited by 707 · see citing works
Regulation and function of miRNA-21 in health and disease
Kumarswamy, R., Volkmann, I. R., & Thum, T. (2011) · RNA Biology · doi:10.4161/rna.8.5.16154 · Cited by 609 · see citing works
Essandoh, K., Li, Y., Huo, J., & Fan, G. (2016) · Shock · doi:10.1097/shk.0000000000000604 · Cited by 603 · see citing works
Turning 21: Induction of miR-21 as a Key Switch in the Inflammatory Response
Sheedy, F. J. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00019 · Cited by 496 · see citing works
The role of PI3K in immune cells
Koyasu, S. (2003) · Nature Immunology · doi:10.1038/ni0403-313 · Cited by 486 · see citing works
Regulation of inflammation by interleukin-4: a review of "alternatives"
Luzina, I. G., Keegan, A. D., Heller, N. M., Rook, G. A. W., Shea-Donohue, T., & Atamas, S. P. (2012) · Journal of Leukocyte Biology · doi:10.1189/jlb.0412214 · Cited by 351 · see citing works
Phenotypic transitions of macrophages orchestrate tissue repair.
Novak, M. L., & Koh, T. (2013) · American Journal of Pathology · doi:10.1016/j.ajpath.2013.06.034 · Cited by 332 · see citing works
Das, A., Ganesh, K., Khanna, S., Sen, C. K., & Roy, S. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1300613 · Cited by 320 · see citing works
Functional significance of macrophage-derived exosomes in inflammation and pain
McDonald, M. K., Tian, Y., Qureshi, R., Gormley, M., Ertel, A., Gao, R. Y., Aradillas, E., Alexander, G. M., Saçan, A., Fortina, P. M., et al. (2014) · Pain · doi:10.1016/j.pain.2014.04.029 · Cited by 319 · see citing works
Molecular and epigenetic basis of macrophage polarized activation
Porta, C., Riboldi, E., Ippolito, A., & Sica, A. (2015) · Seminars in Immunology · doi:10.1016/j.smim.2015.10.003 · Cited by 319 · see citing works
Simeoli, R., Montague-Cardoso, K., Jones, H. R., Castaldi, L., Chambers, D. J., Kelleher, J. H., Vacca, V., Pitcher, T., Grist, J., Alahdal, H. M., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01841-5 · Cited by 311 · see citing works
TGF-β1/Smads and miR-21 in Renal Fibrosis and Inflammation
Łoboda, A., Sobczak, M., Józkowicz, A., & Dulak, J. (2016) · Mediators of Inflammation · doi:10.1155/2016/8319283 · Cited by 298 · see citing works
An NF-κB-microRNA regulatory network tunes macrophage inflammatory responses
Mann, M., Mehta, A., Zhao, J. L., Lee, K., Marinov, G. K., Garcia-Flores, Y., Lu, L.-F., Rudensky, A. Y., & Baltimore, D. (2017) · Nature Communications · doi:10.1038/s41467-017-00972-z · Cited by 275 · see citing works
miR-125a-5p Regulates Differential Activation of Macrophages and Inflammation
Banerjee, S., Cui, H., Xie, N., Tan, Z., Yang, S., Icyuz, M., Thannickal, V. J., Abraham, E., & Liu, G. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.426866 · Cited by 258 · see citing works
Circulating Exosomal MicroRNA-21 as a Biomarker in Each Tumor Stage of Colorectal Cancer
Tsukamoto, M., Iinuma, H., Yagi, T., Matsuda, K., & Hashiguchi, Y. (2017) · Oncology · doi:10.1159/000463387 · Cited by 203 · see citing works
Zhou, R., Hu, G., Gong, A.-Y., & Chen, X. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq056 · Cited by 191 · see citing works
Exosomal miR-21 regulates the TETs/PTENp1/PTEN pathway to promote hepatocellular carcinoma growth
Cao, L., Yang, X., Chen, Y., Zhang, D., Jiang, X., & Xue, P. (2019) · Molecular Cancer · doi:10.1186/s12943-019-1075-2 · Cited by 185 · see citing works
Wang, Z., Brandt, S., Medeiros, A., Wang, S., Wu, H., Dent, A., & Serezani, C. H. (2015) · PLOS ONE · doi:10.1371/journal.pone.0115855 · Cited by 169 · see citing works
Lakhter, A. J., Pratt, R. E., Moore, R. E., Doucette, K. K., Maier, B. F., DiMeglio, L. A., & Sims, E. K. (2018) · Diabetologia · doi:10.1007/s00125-018-4559-5 · Cited by 169 · see citing works
MicroRNA signature in diabetic wound healing: promotive role of miR‐21 in fibroblast migration
Madhyastha, R., Madhyastha, H., Nakajima, Y., Omura, S., & Maruyama, M. (2012) · International Wound Journal · doi:10.1111/j.1742-481x.2011.00890.x · Cited by 168 · see citing works
Self-citationExploring New Inflammatory Biomarkers and Pathways during LPS-Induced M1 Polarization
Cunha, C., Gomes, C., Vaz, A. R., & Brites, D. (2016) · Mediators of Inflammation · doi:10.1155/2016/6986175 · Cited by 153 · see citing works
Lippai, D., Bala, S., Csák, T., Kurt‐Jones, E. A., & Szabó, G. (2013) · PLoS ONE · doi:10.1371/journal.pone.0070945 · Cited by 141 · see citing works
MicroRNA: Dynamic Regulators of Macrophage Polarization and Plasticity
Self-Fordham, J., Naqvi, A. R., Uttamani, J. R., Kulkarni, V., & Nares, S. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01062 · Cited by 140 · see citing works
MiR-21: an environmental driver of malignant melanoma?
Melnik, B. C. (2015) · Journal of Translational Medicine · doi:10.1186/s12967-015-0570-5 · Cited by 129 · see citing works
Cui, H., He, Y., Chen, S., Zhang, D., Yu, Y., & Fan, C. (2018) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2018.11.006 · Cited by 129 · see citing works
The Interplay among miRNAs, Major Cytokines, and Cancer-Related Inflammation
Chakraborty, C., Sharma, A. R., Sharma, G., & Lee, S. (2020) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2020.04.002 · Cited by 114 · see citing works
Strategies for the use of Extracellular Vesicles for the Delivery of Therapeutics
Sil, S., Dagur, R. S., Liao, K., Peeples, E. S., Hu, G., Periyasamy, P., & Buch, S. (2020) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-019-09873-y · Cited by 109 · see citing works
The role of extracellular vesicle microRNAs in cancer biology
Takahashi, R.-U., Prieto-Vila, M., Hironaka, A., & Ochiya, T. (2017) · Clinical Chemistry and Laboratory Medicine · doi:10.1515/cclm-2016-0708 · Cited by 105 · see citing works
New Players in TLR-Mediated Innate Immunity: PI3K and Small Rho GTPases
Ruse, M., & Knaus, U. G. (2006) · Immunologic Research · doi:10.1385/ir:34:1:33 · Cited by 104 · see citing works
Ando, Y., Yang, G., Kenny, T. P., Kawata, K., Zhang, W., Huang, W., Leung, P. S. C., Lian, Z., Okazaki, K., Ansari, A. A., et al. (2013) · Journal of Autoimmunity · doi:10.1016/j.jaut.2012.12.013 · Cited by 98 · see citing works
Recent progress toward the use of circulating microRNAs as clinical biomarkers
Ghai, V., & Wang, K. (2016) · Archives of Toxicology · doi:10.1007/s00204-016-1828-2 · Cited by 89 · see citing works
miRNA in Macrophage Development and Function
Roy, S. (2016) · Antioxidants and Redox Signaling · doi:10.1089/ars.2016.6728 · Cited by 87 · see citing works
Anti-inflammatory effects of miR-21 in the macrophage response to peritonitis
Barnett, R. E., Conklin, D. J., Ryan, L. E., Keskey, R. C., Ramjee, V., Sepulveda, E. A., Srivastava, S., Bhatnagar, A., & Cheadle, W. G. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.4a1014-489r · Cited by 83 · see citing works
Bui, T. M., Mascarenhas, L., & Sumagin, R. (2018) · Tissue Barriers · doi:10.1080/21688370.2018.1431038 · Cited by 73 · see citing works
Shi, Y., Luo, P., Wang, W., Horst, K., Bläsius, F., Relja, B., Xu, D., Hildebrand, F., & Greven, J. (2020) · Inflammation · doi:10.1007/s10753-020-01236-7 · Cited by 54 · see citing works
NFkappaB activation is essential for miR-21 induction by TGFβ1 in high glucose conditions
Madhyastha, R., Madhyastha, H., Pengjam, Y., Nakajima, Y., Omura, S., & Maruyama, M. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.08.035 · Cited by 50 · see citing works
Self-citationIL-4 Up-Regulates MiR-21 and the MiRNAs Hosted in the CLCN5 Gene in Chronic Lymphocytic Leukemia
Ruiz-Lafuente, N., García, M. J. A., Sebastián-Ruiz, S., García‐Serna, A. M., Gómez‐Espuch, J., Moraleda, J. M., Minguela, A., García-Alonso, A.-M., & Parrado, A. (2015) · PLoS ONE · doi:10.1371/journal.pone.0124936 · Cited by 48 · see citing works
Melnik, B. C., John, S. M., Carrera‐Bastos, P., & Schmitz, G. (2020) · Cancers · doi:10.3390/cancers12082111 · Cited by 43 · see citing works
NF-κB activation plays an important role in the IL-4-induced protection from apoptosis
Zamorano, J., Mora, A. L., Boothby, M. R., & Keegan, A. D. (2001) · International Immunology · doi:10.1093/intimm/13.12.1479 · Cited by 42 · see citing works
Pengjam, Y., Madhyastha, H., Madhyastha, R., Yamaguchi, Y., Nakajima, Y., & Maruyama, M. (2016) · Phytomedicine · doi:10.1016/j.phymed.2016.01.006 · Cited by 39 · see citing works
Self-citationSoeda, N., Iinuma, H., Suzuki, Y., Tsukahara, D., Midorikawa, H., Igarashi, Y., Kumata, Y., Horikawa, M., Kiyokawa, T., Fukagawa, T., et al. (2019) · Oncology Letters · doi:10.3892/ol.2019.10807 · Cited by 34 · see citing works
Co-Detection of miR-21 and TNF-α mRNA in Budding Cancer Cells in Colorectal Cancer
Møller, T., James, J. P., Holmstrøm, K., Sørensen, F. B., Lindebjerg, J., & Nielsen, B. S. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20081907 · Cited by 32 · see citing works
Bakirtzi, K., Law, I. K. M., Fang, K., et al. (2019) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00043.2019 · Cited by 32 · see citing works
The pivotal role of microRNA-21 in osteoclastogenesis inhibition by anthracycline glycoside aloin
Madhyastha, R., Madhyastha, H., Pengjam, Y., et al. (2018) · Journal of Natural Medicines · doi:10.1007/s11418-018-1237-3 · Cited by 27 · see citing works
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Garcia, G., Pinto, S., Ferreira, S., Lopes, D., Serrador, M. J., Fernandes, A., Vaz, A. R., Mendonça, A. D., Edenhofer, F., Malm, T., et al. (2022) · Cells · doi:10.3390/cells11213377 · Cited by 55 · see citing works
“In this condition, only miR-21 was found to be enriched in their derived exosomes and may further elicit a pro-inflammatory response [123].”
BackgroundMicroRNAs as Regulators of Phagocytosis
Gierlikowski, W., & Gierlikowska, B. (2022) · Cells · doi:10.3390/cells11091380 · Cited by 25 · see citing works
- Authors
- Madhyastha, R., Madhyastha, H., Nurrahmah, Q. I., Purbasari, B., Maruyama, M., & Nakajima, Y.
- Affiliations
- University of Miyazaki (JP)
- Corresponding author
- Madhyastha, Radha
- Nakajima, Yuichi
- ORCID
- Venue
- Inflammation
- Published
- 2021-01-26
- Volume
- 44
- Issue
- 4
- Pages
- 1274-1287
- ISSN
- 0360-3997 (ISSN-L)
- 1573-2576
- OpenAlex
- W3121400137
- Semantic Scholar
- 60709ff8fa0dff9c937cc4a4340bf1aa4b61c475
- Cited by
- 53
- References
- 53
- Citations by year
- 2026: 11 · 2025: 9 · 2024: 4 · 2023: 12 · 2022: 10 · 2021: 7
- FWCI
- 2.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Inflammation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology (19K10010)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- miR-21, microRNA, macrophage polarization, pro-inflammatory response, exosomes, exosomal microRNA delivery, paracrine signaling, PI3K signaling, NF-κB signaling, inflammatory cytokines, RAW 264.7 macrophages, inflammatory markers, therapeutic target
- MeSH terms
- RAW 264.7 Cells, Animals, Cell Communication, Macrophages, Phagocytosis, Cell Polarity, Inflammation Mediators, MicroRNAs, Mice, Exosomes
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