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Mycobacterium tuberculosis lipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b
Open accessAbstract
Contact of Mycobacterium tuberculosis (M.tb) with the immune system requires interactions between microbial surface molecules and host pattern recognition receptors. Major M.tb-exposed cell envelope molecules, such as lipomannan (LM), contain subtle structural variations that affect the nature of the immune response. Here we show that LM from virulent M.tb (TB-LM), but not from avirulent Myocobacterium smegmatis (SmegLM), is a potent inhibitor of TNF biosynthesis in human macrophages. This difference in response is not because of variation in Toll-like receptor 2-dependent activation of the signaling kinase MAPK p38. Rather, TB-LM stimulation leads to destabilization of TNF mRNA transcripts and subsequent failure to produce TNF protein. In contrast, SmegLM enhances MAPK-activated protein kinase 2 phosphorylation, which is critical for maintaining TNF mRNA stability in part by contributing microRNAs (miRNAs). In this context, human miRNA miR-125b binds to the 3' UTR region of TNF mRNA and destabilizes the transcript, whereas miR-155 enhances TNF production by increasing TNF mRNA half-life and limiting expression of SHIP1, a negative regulator of the PI3K/Akt pathway. We show that macrophages incubated with TB-LM and live M.tb induce high miR-125b expression and low miR-155 expression with correspondingly low TNF production. In contrast, SmegLM and live M. smegmatis induce high miR-155 expression and low miR-125b expression with high TNF production. Thus, we identify a unique cellular mechanism underlying the ability of a major M.tb cell wall component, TB-LM, to block TNF biosynthesis in human macrophages, thereby allowing M.tb to subvert host immunity and potentially increase its virulence.
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“upon Mtb infection, contrary changes occur, i.e., up-regulation of miR-125b and down-regulation of miR-155 decreases TNF production [142]”
From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [142]
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Epigenetic regulation of macrophages: from homeostasis maintenance to host defense
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Metadata
- Authors
- Rajaram, M. V. S., Ni, B., Morris, J. D., Brooks, M. N., Carlson, T. K., Bakthavachalu, B., Schoenberg, D. R., Torrelles, J. B., & Schlesinger, L. S.
- Affiliations
- Center for Microbial Interface Biology,
- Integrated Biomedical Science Graduate Program,
- Center for RNA Biology and Department of Molecular and Cellular Biochemistry,
- The Ohio State University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-10-03
- Volume
- 108
- Issue
- 42
- Pages
- 17408-17413
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3198317
- OpenAlex
- W2101417884
- Cited by
- 269
- References
- 43
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 3 · 2023: 20 · 2022: 15 · 2021: 20 · 2020: 19 · 2019: 16 · 2018: 19 · 2017: 18 · 2016: 35 · 2015: 26 · 2014: 23 · 2013: 26 · 2012: 16
- FWCI
- 14.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (8k01od011077-03)
- National Institute of General Medical Sciences (R01GM038277, GM038277)
- National Institute of Allergy and Infectious Diseases (AI059639, R01AI059639, AI-052458, R01AI052458, R21AI059639, R21AI052458)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- Mycobacterium tuberculosis, lipomannan, macrophages, MAPKAPK2, miR-125b, miR-155, 3' untranslated region, SHIP1, PI3K/Akt signaling, Mycobacterium smegmatis, virulence, host immune evasion
- MeSH terms
- Humans, Lipopolysaccharides, Macrophages, Mycobacterium tuberculosis, Phosphorylation, Promoter Regions, Genetic, Tumor Necrosis Factor-alpha, Virulence, RNA Stability, MAP Kinase Signaling System, MicroRNAs, p38 Mitogen-Activated Protein Kinases, MAP Kinase Kinase 2, Proto-Oncogene Proteins c-akt, Toll-Like Receptor 2, In Vitro Techniques
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