MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment

Anca Dorhoi, Marco Iannaccone, Maura Farinacci, Kellen C. Faé, Jörg Schreiber, Pedro Moura-Alves, Geraldine Nouailles, Hans Joachim Mollenkopf, Dagmar Oberbeck-Müller, Sabine Jörg, Ellen Heinemann, Karin Hahnke, Delia Löwe, Franca Del Nonno, Delia Goletti, Rosanna Capparelli, Stefan H E Kaufmann

Research output: Contribution to journalArticle

Abstract

The molecular mechanisms that control innate immune cell trafficking during chronic infection and inflammation, such as in tuberculosis (TB), are incompletely understood. During active TB, myeloid cells infiltrate the lung and sustain local inflammation. While the chemoattractants that orchestrate these processes are increasingly recognized, the posttranscriptional events that dictate their availability are unclear. We identified microRNA-223 (miR-223) as an upregulated small noncoding RNA in blood and lung parenchyma of TB patients and during murine TB. Deletion of miR-223 rendered TB-resistant mice highly susceptible to acute lung infection. The lethality of miR-223-/- mice was apparently not due to defects in antimycobacterial T cell responses. Exacerbated TB in miR-223-/- animals could be partially reversed by neutralization of CXCL2, CCL3, and IL-6, by mAb depletion of neutrophils, and by genetic deletion of Cxcr2. We found that miR-223 controlled lung recruitment of myeloid cells, and consequently, neutrophil-driven lethal inflammation. We conclude that miR-223 directly targets the chemoattractants CXCL2, CCL3, and IL-6 in myeloid cells. Our study not only reveals an essential role for a single miRNA in TB, it also identifies new targets for, and assigns biological functions to, miR-223. By regulating leukocyte chemotaxis via chemoattractants, miR-223 is critical for the control of TB and potentially other chronic inflammatory diseases.

Original languageEnglish
Pages (from-to)4836-4848
Number of pages13
JournalJournal of Clinical Investigation
Volume123
Issue number11
DOIs
Publication statusPublished - Nov 1 2013

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Dorhoi, A., Iannaccone, M., Farinacci, M., Faé, K. C., Schreiber, J., Moura-Alves, P., Nouailles, G., Mollenkopf, H. J., Oberbeck-Müller, D., Jörg, S., Heinemann, E., Hahnke, K., Löwe, D., Del Nonno, F., Goletti, D., Capparelli, R., & Kaufmann, S. H. E. (2013). MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment. Journal of Clinical Investigation, 123(11), 4836-4848. https://doi.org/10.1172/JCI67604