MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment
Anca Dorhoi, … , Rosanna Capparelli, Stefan H.E. Kaufmann
Anca Dorhoi, … , Rosanna Capparelli, Stefan H.E. Kaufmann
Published October 1, 2013
Citation Information: J Clin Invest. 2013;123(11):4836-4848. https://doi.org/10.1172/JCI67604.
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Research Article Pulmonology

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

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.

Authors

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

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Figure 3

Deletion of miR-223 renders resistant mice susceptible to TB.

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Deletion of miR-223 renders resistant mice susceptible to TB. (A) Surv...
(A) Survival of miR-223 KO (miR-223–/–) mice and C57BL/6 (WT) littermates after aerosol infection with Mtb (~200 CFUs). Data are representative of two independent experiments; Kaplan–Meier curves and log-rank test (n = 12). (B) Kinetics of bacterial load in lungs of infected mice. Data are presented as the median ± the interquartile range (iQR) and are representative of three independent experiments; Mann-Whitney U test (n = 5–6); **P < 0.01. (C) Large infiltration foci in lung (left panels, Giemsa staining) and numerous bacilli (right panels, acid-fast staining) in the absence of miR-223. Tissues were collected on days 21 and 25 p.i., respectively. Data are representative of two independent experiments. Scale bars: 1,000 μm (left panels) and 10 μm (right panels) (n = 5). (D) Immunohistochemistry for iNOS in lung tissue collected 21 days p.i. Data are representative of two independent experiments (n = 5). Scale bars: 100 μm. (E) Left panels: representative dot plots of CD4+ and CD8+ lymphocytes isolated on day 21 p.i. and stimulated with PPD or CD3/CD28 and then stained for intracellular TNF-α and IFN-γ. Right panels: frequency of cells double-positive for TNF-α and IFN-γ. Data are presented as the mean ± SEM and are pooled from two independent experiments (n = 8–9).