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Pseudomonas aeruginosa infection augments inflammation through miR-301b repression of c-Myb-mediated immune activation and infiltration

Nature Microbiology volume 1, Article number: 16132 (2016) Cite this article

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Abstract

MicroRNAs (miRNAs) play critical roles in various biological processes, including cell proliferation, development and host defence. However, the molecular mechanism for miRNAs in regulating bacterial-induced inflammation remains largely unclear. Here, we report that miR-301b augments pro-inflammatory response during pulmonary infection, and caffeine suppresses the effect of miR-301b and thereby augments respiratory immunity. LPS treatment or Pseudomonas aeruginosa infection induces miR-301b expression via a TLR4/MyD88/NF-κB pathway. Importantly, caffeine decreases miR-301b expression through negative regulation of the cAMP/PKA/NF-κB axis. Further, c-Myb is identified as a target of miR-301b, which positively modulates anti-inflammatory cytokines IL-4 and TGF-β1, but negatively regulates pro-inflammatory cytokines MIP-1α and IL-17A. Moreover, repression of miR-301b results in increased transcription of c-Myb and elevated levels of neutrophil infiltration, thereby alleviating infectious symptoms in mice. These findings reveal miR-301b as a new controller of inflammatory response by repressing c-Myb function to inhibit the anti-inflammatory response to bacterial infection, representing a novel mechanism for balancing inflammation.

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Figure 1: CAF decreases miR-301b, 301a and 15a expression.
Figure 2: CAF inhibits LPS-induced miR-301b expression by regulating the cAMP/PKA/CREM/NF-κB axis.
Figure 3: Enforced expression of miR-301b suppresses bacterium-induced anti-inflammatory responses in vivo.
Figure 4: c-Myb is a functional target of miR-301b.
Figure 5: c-Myb plays a role in mediating infection-induced inflammatory responses.
Figure 6: CAF and 301b-i decrease susceptibility and mortality after pulmonary bacterial infection.

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Acknowledgements

This work was supported by the National Institutes of Health (AI109317-01A1 and AI101973-01) to M.W., and by grants from the National 973 Basic Research Program of China (2013CB911300), the Chinese NSFC (81225015 and 81430071) and Sichuan Science–Technology Innovative Research Team for Young Scientist (2013TD0001) to C.H. The authors thank S. Abrahamson of the UND imaging core for help with confocal imaging.

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Author notes

  1. Xuefeng Li, Sisi He, Rongpeng Li and Xikun Zhou: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Sciences, University of North Dakota, Grand Forks, 58203-9037, North Dakota, USA

    Xuefeng Li, Sisi He, Rongpeng Li, Xikun Zhou, Shuang Zhang, Min Yu, Yan Ye & Min Wu

  2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China

    Xuefeng Li, Sisi He, Xikun Zhou, Shuang Zhang, Yongsheng Wang & Canhua Huang

  3. Department of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu 610041, China

    Min Yu

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Contributions

X.L., S.H., C.H. and M.W conceived and designed the experiments. X.L., S.H., R.L. and X.Z. performed the experiments. X.L., S.H., R.L., X.Z., S.Z., M.Y., Y.Y. and Y.W. analysed the data. C.H. and M.W. contributed reagents, materials and analysis tools. X.L., S.H., C.H. and M.W. wrote the manuscript.

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Correspondence to Canhua Huang or Min Wu.

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The authors declare no competing financial interests.

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Li, X., He, S., Li, R. et al. Pseudomonas aeruginosa infection augments inflammation through miR-301b repression of c-Myb-mediated immune activation and infiltration. Nat Microbiol 1, 16132 (2016). https://doi.org/10.1038/nmicrobiol.2016.132

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